



































Inhibitors of Apoptosis Proteins as 
Potential Research Targets for 
Decoding the Pathological Mechanisms 
of Autoimmune Diseases 
By: Kezia Philip, Hoc Lan Phung and Vanloan Nguyen

Berkeley 
Pharma Tech
Journal of Medicine

Correspondence 
keziaphilip.bpt@gmail.com

Keywords 
Apoptosis 
Necrosis 
Necroptosis 
Autoimmune diseases 
Caspases

Submitted June 28, 2021 
Accepted August 20, 2021 
Published December 17, 2021

Full Open Access

Creative Commons 
Attribution License 4.0

An artist's rendition of a cell undergoing apoptosis. Image Credits: Kateryna Kon / Shutterstock.com

Abstract
Necroptosis, a type of pathological and inflammatory cell death, resembles 
necrosis, the  termination of function of a bodily tissue, but adopts a 
unique molecular pathway that is not like apoptosis, resulting in vastly 
different immunological consequences. Until recently, necroptosis  was 
believed to mainly function as a protective mechanism that counteracts the viral 
barrier of  apoptosis. However, mouse model studies have indicated that 
deficiency in elements of the  apoptosis machinery such as caspase-8 or FADD 
can result in embryonic lethality driven by  necroptosis. Previous studies using 
conditional depletion of cellular inhibitors of apoptosis  (cIAPs) revealed that the 
necroptosis pathway is triggered under certain stressor conditions.  These 
data support a new approach of targeting molecules within the cell death 
pathways to  identify the origin of autoimmune diseases. Hence, 
distinguishing between these two types of  cell death may prove crucial 
during pathologic evaluations. This review provides a detailed insight into 
the emerging discussion on the various forms of cell death and the essential 
roles  which certain molecules play in the development and progression 
of autoimmune diseases.  Armed with this knowledge, greater efforts can 
be targeted towards devising more effective  treatments for interception 
of pathological diseases, prior to their uncontrollable progression. 



Introduction

Over the last decade, advances in cell death research have greatly 
contributed to our understanding of cell death. Dysregulation of cell 
death has been found to be critically involved in the onset of various 
human diseases, such as neurodegenerative diseases1, autoimmune 
diseases2, and cancer3. The three forms of cell death of interest –
apoptosis2,4,5,6, necrosis7,8,9, and necroptosis3,10 – have distinct features and 
activate unique signaling pathways. Apoptosis is a caspase-mediated 
programmed cell death that can be identi ed by chromosome 
condensation, nuclear fragmentation, and membrane blebbing2. 
Conversely, necrosis is an unregulated, accidental form of cell death, 
triggered by non-physiological stress inducers and characterized by the 
expansion of cellular organelles, plasma membrane rupture, and 
subsequent in ammatory responses caused by the release of the 
intracellular contents7,8.

The recent identi cation of necroptosis has transformed our 
understanding of regulated cell death. It has become increasingly evident 
that although the di erent types of cell death have distinctive 
characteristics, they are ultimately interconnected. Thus, the activation or 
inhibition of a particular signaling molecular pathway under certain 
conditions determines the regulation or dysregulation of another 
associated cell death mechanism11,12,13,14. In this review, we focus on the 
speci c mechanisms involved in each particular type of cell death and the 
connections between them. By highlighting the pathophysiological 
relevance of necroptosis and the key roles of certain cell mediators and 
signaling molecules, we are proposing a new perspective for consequent 
medical research that investigates the pathogenesis of various diseases 
across the body, including neurological13,15, cardiovascular16, pulmonary, 
gastrointestinal, infectious, and autoimmune3,17,18 conditions, all of which 
have been linked to necroptosis.

Cell    Death and  Autoimmune  Disorders

Programmed cell death is an intricate biological element that plays a vital 
role in several physiological processes, including homeostasis, regulation of 
the immune system, and disease pathogenesis1. It involves multiple 
pathways and is regulated by various intrinsic cell death programs. Over 
the past two decades, extensive research has transformed the understanding 
of programmed cell death and the di erent mechanisms that control it.

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Initially, apoptosis was believed to be the only form of programmed cell
death, whereas necrosis was considered unregulated and resulting from a
damaged environmental stress response3. However, emerging experimental
evidence reveals a regulated form of necrosis, termed necroptosis, a form of
cell death controlled by speci c intrinsic programs. Autoimmune
disorders, such as rheumatoid arthritis, can result from defects in multiple
stages of these forms of cell death, ranging from mutant death receptors
and ligands to speci c biochemical changes in death-inducing signaling
molecules2. Closely examining these complex mechanisms is very essential
in gaining a better understanding of the pathogenesis of rheumatoid
arthritis and several other autoimmune  disorders.

Table 1: Comparison between morphological features of apoptosis, necrosis, and necroptosis

Apoptosis
Apoptosis is an intracellular process that occurs during cellular 
development, providing a homeostatic mechanism to remove damaged 
cells3,4,5,6. Cells undergoing apoptosis display morphological characteristics 
such as plasma membrane blebbing, chromosome condensation, nuclear 
fragmentation, formation of apoptotic bodies, and cell shrinkage. In the 
early stages of the disease, they also exhibit biochemical changes, such as 
the exposure of phosphatidyl-l-serine on the outer plasma 
membrane19,20,21. The mechanism of apoptosis involves certain molecules 
that play an important role in mediating cell death.

Apoptosis involves an energy-dependent cascade of molecular events that 
results from three primary pathways: the extrinsic (cell death) receptor

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pathway, the intrinsic (mitochondrial) pathway, and the stress-induced 
pathway in the endoplasmic reticulum22. Despite having di erent initiator 
caspases (caspase-8, caspase-9, and caspase-10), all of these pathways are 
linked via caspase-3 activation of downstream molecules1. The activation of 
the death receptor-mediated apoptosis pathway occurs when the Fas ligand, 
TNF-α (tumor necrosis factor α), binds to the corresponding death 
receptors11,12. The adaptor protein FADD11,23, and the procaspase-8 protein 
form a complex, the death-inducing signaling complex (DISC), in which 
procaspase-8 is activated by autohydrolysis24,25. The activated caspase-8 
then transduces the apoptosis signal through, either the activation of 
caspase-3, or the cleavage of BID to truncated BID (tBID). tBID 
translocates to the mitochondria, resulting in conformational changes in 
Bax and Bak, as well as their oligomerization for pore formation in the 
outer mitochondrial membrane25,26.

Stress inducers such as DNA damage, growth factor withdrawal, and 
oxidative stress activate the mitochondrial-dependent pathway27,28. This 
intrinsic pathway is controlled by the Bcl-2 family of proteins, which 
regulates the permeability of the outer mitochondrial membrane29,30,31. 
Upon release into the cytoplasm from the mitochondria, cytochrome c 
combines with Apaf-1 to promote caspase-9 activation, which, in turn, 
activates e ector caspases32,33 to trigger a cascade of  proteolytic events.

The ER-dependent pathway is mediated by an ER-resistant caspase 
(caspase-12). It is activated under the presence of ER stresses: the 
disturbance of calcium homeostasis, excessively unfolded or misfolded 
protein accumulation, nutrient deprivation, and hypoxia22. Activated 
caspase-12 directly cleaves caspase-9 after its translocation from the ER into 
the cytosol, followed by the activation of caspase-334. Similarly, forming a 
complex with the inositol requiring enzyme-1α-TNF receptor-associated 
factor 2 (TRAF2), or by calpains, a family of Ca2+-dependent intracellular 
cysteine proteases, activates the caspase-12 during ER stress.7,35.

Together, these pathways result in phagocytosis of the apoptotic bodies by 
macrophages, neoplastic cells, or neighboring parenchymal cells24. 
Interestingly, caspase-3 is the common factor linking these 3 pathways 
together, initiating the apoptosis execution pathway upon activation8. 
This marks caspase-3 as the potential target for studying the divergence of 

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each pathway, allowing for the manipulation of apoptosis. 
Understanding the morphological and cellular characteristics of apoptotic 
mechanisms, as well as identifying the key molecules involved in mediating 
cell death, is integral in discerning their roles in autoimmune diseases.

Figure 1: Mechanisms of Apoptosis

Table 2: Names and abbreviations of proteins in the extrinsic, 
intrinsic, and ER-dependent  pathways of apoptosis.

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Apoptosis and Disease
The repression of apoptosis increases the possibility of malignancy, as it 
inhibits tumor cell deaths. On the other hand, uncontrolled apoptosis is 
associated with various degenerative diseases including acquired 
immunode ciency syndrome36, cancer2, Parkinson's disease37 and 
Alzheimer's disease38. Additionally, apoptosis has been correlated with 
HIV39, Type 1 diabetes41,42, autoimmune thyroid diseases, systemic lupus 
erythematosus, rheumatoid arthritis,  and Sjogren’s syndrome.

Controlled apoptosis regulates normal T-cell selection and function. In 
turn, type 1 diabetes is caused by the insulin-secreting β-cells of the 
pancreas being attacked by T-cells. The FOXP3+CD4+CD25high T-cells 
(Tregs) represent one of the best characterized sub populations of 
regulatory T-cells that actively suppress e ector T-cells. The increasing 
evidence of Tregs de ciency in various autoimmune diseases3, as well as in 
Type 1 diabetes41,42, suggests a correlation between greater levels of Tregs 
apoptosis and a decline in suppressive potential of these cells. However, the 
data collected are not always consistent in these studies since the 
investigations are conducted in di erent phases of the diseases and with 
various ongoing immunosuppressive therapies. Most of these studies also 
have limitations in terms of distinguishing nTreg cells from activated Te  
cells and characterizing their suppressive function. Current studies fail to 
elucidate the pathways and genes that make Tregs sensitive to apoptosis 
during the progression of the disease.

Recent evidence supports the involvement of the Fas and TRAIL mediated 
apoptotic pathways in the autoimmune diseases of the thyroid17,18. One of 
the earliest breakthroughs occurred when Giordano et al. (1997) used 
immunohistochemistry, ow cytometry, and RT-PCR to discover the 
constitutive expression of FasL (Fas ligand) on normal and Hashimoto's 
thyroiditis (HT) thyrocytes43,44. Although thyrocytes are known to express 
the death receptor Fas, not much is known about how the expression is 
modulated. Upregulation of Fas was also found in the thyrocytes of 
patients with Graves’ disease. Discoveries like these strongly support the 
theory that apoptosis and the proliferation of thyrocytes may be 
abnormally accelerated in patients with thyroid disease, although the 
proliferation of thyrocytes may exceed their apoptosis, which would result 
in hyperplasia.

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Another autoimmune disease, systemic lupus erythematosus (SLE), is 
linked to apoptosis through an increased number of apoptotic 
lymphocytes and macrophages observed in patients with SLE45. 
Characterized by the declining tolerance of self-antigens, this disease causes 
the production of antibodies, reactive with multiple self proteins46. 
Apoptosis is crucial for regulating the duration of immune responses and 
maintaining the diversity of the lymphoid armamentarium. Based on 
considerable statistical data, studies have identi ed that the de ciency of 
central molecules involved in lymphocyte apoptosis causes 
lymphoproliferative and autoimmune diseases in mice and humans47,48. In 
rheumatoid arthritis (RA) tissues in vitro, synoviocytes, synovial T cells 
and macrophages have been found to express high levels of Fas and/or 
FasL and are highly susceptible to Fas/FasL-induced apoptosis. 
Conversely, abnormalities in Fas/FasL expression and susceptibility to 
Fas-induced apoptosis are generally not observed in osteoarthritis49. In 
some studies, invading T cells have been observed to be defective in 
FasL expression, which could explain the ine ective clearance of 
activated (Fas-expressing) cells. Additionally, rheumatoid synovial 
uid contains high levels of caspase-3 inhibiting nitric oxide. 

Therefore, though these studies indicate that Fas induced apoptosis is 
impaired in RA joints, they do not explain whether these phenomena 
are a direct result of the initial in ammatory pathways of RA or whether 
they underlie the disease etiology.

Apoptosis evidently plays a valuable role in the pathogenesis of several of 
the autoimmune diseases. The extent of apoptotic regulation dictates the 
pathological manifestations of these diseases. Considerably repressed 
apoptosis increases the likelihood of malignancy, whereas unregulated 
apoptosis can directly lead to the initiation and progressions of several 
autoimmune diseases. The exact molecules and cellular targets determine 
the type of degenerative disease. Thus, studies discovering the functions 
and mechanisms of cell mediators involved in cell death are crucial to 
elucidating the pathogenesis of autoimmune diseases.

Necrosis
Necrosis is an unregulated or accidental cell death due to internal or 
external stresses, resulting from the disruption of membrane homeostasis 
It leads to water imbalance between the extracellular and intracellular 
environments50,51,52. Recently it has been suggested that a programmed

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form of necrosis, commonly known as necroptosis, is a critical pathway 
that is involved in a number of autoimmune diseases, as well as heart 
diseases. The discovery of necroptosis signi es the need to di erentiate 
between the mechanisms that induce passive necrosis, and those that 
stimulate necroptosis, to better understand disease progression8,9. 
Although necrosis and necroptosis share nearly identical characteristics, the 
implication of necroptosis in several diseases raises a topic of interest in 
research studying autoimmune  diseases.

Although there are some morphological and mechanistic di erences 
between apoptosis and necrosis, these two processes overlap in some ways. 
Evidence indicates that necrosis and apoptosis share a biochemical 
network described as the “apoptosis-necrosis continuum.”53 For example, a 
decrease in the availability of caspases, or intracellular ATP, can convert an 
ongoing apoptotic process into a necrotic process54,55. The tissue type, the 
nature of the cell death signal, the physiological make up, and the 
developmental stage of the tissue all determine whether a cell dies by 
necrosis, or apoptosis53,56. Using conventional histology to distinguish 
between apoptosis and necrosis proves di cult, as they can occur 
simultaneously depending on factors such as the availability of caspases, 
the intensity and duration of the stimulus, and the extent of ATP 
depletion53.

One of the primary di erences is that necrosis is an unregulated, passive 
process that usually impacts a large range of cells. Apoptosis is contained, 
energy-dependent, and can a ect clusters or individual cells. Necrosis is 
initiated by two main mechanisms: interference with the energy supply of 
the cell and direct damage to cell membranes. On the other hand, there is 
virtually no in ammatory reaction in apoptotic cells, because they do not 
release their cellular constituents into the surrounding interstitial tissue 
and are quickly phagocytosed by  macrophages or adjacent normal cells57,58.

Necroptosis
Necroptosis di ers from apoptosis in several ways. Cellls undergoing 
apoptosis maintain the integrity of their cell membrane, whereas 
necroptosis disrupts the cell membrane. Although apoptosis and 
necroptosis share certain triggers, the intracellular signaling pathways that 
ultimately lead to each cascade di er16. Apoptosis is known to be regulated 
by key mediators called caspases, whereas the main mediators of

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necroptosis are receptor-interacting protein kinases (RIPKs). Additionally, 
apoptosis and necroptosis intersect at several points during the signal 
transduction process. One of the most well-researched convergence points 
between the two processes is the role of caspase-8 in inhibiting necroptosis 
by cleaving necroptosis  mediators59,60.

In simple terms, necroptosis is a cellular response to environmental stress, 
triggered by mechanical or chemical injury, in ammation, or infection. The 
existing knowledge of necroptosis revolves around a key signaling 
molecular pathway: the TNF-α receptor system — a pleiotropic molecule 
capable of inducing a survival, apoptotic, or necroptotic response based 
upon the assembly of various sequential cell death complexes61,62. Under 
some cellular conditions, the binding of the ligand TNF-α to the receptor 
TNF-RI triggers the formation of complex I (a prosurvival complex that 
signals through NF-κB). However, in cases where RIPK1 is de 
ubiquitinated, the complex has become an apoptotic complex IIa63. 
Furthermore, the absence of caspase 8, in addition to elevated levels of 
Receptor-interacting serine/threonine-protein kinase 3 (RIPK3), alter the 
complex to IIb (also called the necrosome). This necrosome contains 
RIPK1, RIPK3 and the Fas-associated protein with death domain, allowing 
the cell to undergo necroptosis via direct phosphorylation of mixed lineage 
kinase domain-like protein (MLKL) by RIPK364,65. Phosphorylation of 
MLKL results in a pore-forming oligomer that punctures the  plasma 
membrane and causes subsequent cell death66.

Figure 2: TNFR1-mediated cell death and survival pathways

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A number of proin ammatory cytokines, such as the key mediators of 
necroptosis, TNF-α and IL-1β, as well as in ammatory cells, can cause cell 
death67. However, the pathological manifestation of in ammation varies 
according to the type of cell death. Apoptosis generates a milder 
in ammatory response because it maintains the integrity of the cell 
membrane and avoids the overspill of intracellular contents68. Conversely, 
necroptosis directly activates and regulates in ammatory responses by 
releasing intracellular contents through the ruptured plasma membrane. 
The strong connection found between necroptosis and in ammation has 
been thought to be the primary component of the pathogenesis of 
necroptosis associated diseases. Moreover, RIPK1 and RIPK3 have been 
found to incite an in ammatory response regardless of cell death69,70. These 
distinguishable characteristics of necroptosis draw interest to their 
implication in the progression of autoimmune diseases.

Necroptosis in A  utoimmune  Diseases
The examination of certain neurodegenerative diseases, such as Alzheimer’s 
disease (AD), multiple sclerosis (MS), and amyotrophic lateral sclerosis 
(ALS), have contributed to the study of the implications of necroptosis71. 
Alzheimer’s disease (AD) is a degenerative brain disease, which is 
characterized by the damage and loss of neurons. A study examining 
human AD brains and mouse model AD brains72 con rmed the activation 
of necroptosis73 after observing a major increase in the level of necroptosis 
markers — RIPK1, MLKL, necrosome complex and MLKL oligomers —
in AD brains compared to normal. Subsequently treating mice with AD 
brains with the necroptosis inhibitor, Cl-O-necrostatin, signi cantly 
suppressed necroptosis and prevented neuronal loss73. This suggests that 
inhibiting the function of necrosome components interferes with the 
activation of necroptosis, highlighting a promising strategy in the 
treatment of AD. In some reports, apoptotic morphology was not directly 
observed in any sections of the brain. Instead, the cells showed swollen 
morphologies and were positive for DNA fragmentation, implying that 
AD pathogenesis may not involve apoptosis. Others have argued that the 
apoptosis theory and the clinical manifestations contradict each other. 
Cells directed to apoptosis have shown to die within days, and with great 
levels of caspase-3 activity, suggesting an acute and massive neuronal loss 
according to the apoptosis theory. In such cases, the clinical symptoms of 
AD patients should be observed in the early phase of the disease rather than

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assessing the progression of the disease over a decade.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative 
disease characterized by the loss of motor neurons. Compared to healthy 
control spinal cords, the ALS spinal cords showed an increase in necrosome 
components, including RIPK1, RIPK3 and MLKL, in a mouse model of 
ALS15. Furthermore, inhibiting RIPK1 with Nec-1, or knocking-out 
RIPK3, protected against demyelination and prevented the progression of 
the disease15. Thus, through promoting in ammation and cell death, 
RIPK1 and RIPK3 induce axonal degradation and act as mediators of 
ALS and PD. This further indicates that, since necroptosis is activated in 
ALS, inhibition of necroptosis can be a potential therapeutic target for 
this disease. Additionally, a study observing a Parkinson's disease (PD) 
model found that upon inhibition of RIPK1 by Nec-113 neuronal 
degradation was reduced by a half, compared to untreated cells. The 
protective e ect of Nec-1 indicates the therapeutic potential of this drug 
in ALS and PD. The study used a human iPSC based model to e ectively 
capture both early pathological events in mutant neural cells and the 
bene cial e ects of blocking necroptosis, thereby, strengthening the 
validity of the results.

Multiple Sclerosis (MS) is a chronic neurodegenerative disease 
characterized by the loss of oligodendrocytes and demyelination. High 
concentrations of necroptosis components, including phosphorylation of 
RIPK1, RIPK3 and MLKL, were detected in pathological samples from 
MS patients, as well as a prominent increase of MLKL oligomers in MS 
pathological samples compared to the control40. This indicates that 
necroptosis is also involved in the pathogenesis of MS40. In the study, oral 
administration of RIPK1 inhibitor 7-Cl-O Nec-1 diminished 
oligodendrocyte degeneration and reduced the disease severity in a mouse 
model of MS

40. These ndings reveal that inhibiting RIPK1 speci cally 
could be of potential therapeutic value in the treatment of MS. Although 
the study does not take into consideration the potential metabolic 
consequences of orally administering the drug, their results and conclusion 
are strongly supported by signi cant amounts of experimental data. 
Rheumatoid arthritis (RA) is one of the most common chronic 
in ammatory diseases that is characterized by joint in ammation and 
osteoclastogenesis. The key regulators of necroptosis, RIPK1, RIPK3 and 
MLKL were detected in signi cantly higher amounts in the synovium of a 
collagen-induced arthritis mouse model displayed signi cantly higher

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amounts of the key regulators of necroptosis, RIPK1, RIPK3 and MLKL, 
which emphasized the involvement of necroptosis in the pathogenesis of 
RA14. In the mouse model, RIPK1 inhibitor Nec-1 greatly suppressed the 
expression of these key regulators and the main in ammatory cytokines, 
IL-17, IL-1β, IL-6 and TNFα74. Therefore, similarly to the previous 
conclusions, this study supports the potential of inhibiting RIPK1 as a 
novel therapeutic approach for the treatment of RA.

Although these studies provide compelling evidence for targeting RIPK1 
and MLKL molecules for subsequent therapeutic research, a close 
examination of another class of proteins that play an important role in 
necroptosis may shed light on another new approach. Inhibitors of 
apoptosis proteins (IAPs) form a family of genetically conserved proteins 
characterized by the presence of 1-3 baculovirus IAP repeat (BIR) 
motifs75. Previous studies have identi ed three family members (termed 
XIAP, cIAP1, and cIAP2) as potent suppressors of cell death. XIAP, the 
most-studied IAP, inhibits apoptosis by binding and inhibiting caspases, 
and it has been broadly assumed that cIAP1 and cIAP2 block apoptosis 
through a similar mechanism. However, recent structure function analyses 
have indicated that these IAPs are not direct caspase inhibitors, suggesting 
that their anti-apoptotic function must involve alternative mechanisms75.

Cellular   Inhibitors of  Apoptosis
Inhibitors of apoptosis (IAP) are proteins that belong to the family of 
antiapoptotic proteins that prevent cell death, direct cell growth, and 
participate in cellular signal transduction76. The mechanism of IAPs in 
inhibiting apoptosis involves both the intrinsic and extrinsic apoptotic 
pathways1. Among these IAPs, cellular IAP1 and 2 (cIAP1 and cIAP2), the 
key molecules of the tumor necrosis factor α (TNFα) signaling pathway, are 
recruited upon TNF receptor (TNF1) activation, along with the other 
adaptor proteins such as TNF receptor-associated factor (TRAF), TNFR-
associated death domain protein (TRADD), receptor-interacting protein 
kinase 1 (RIPK1) and linear ubiquitin chain assembly complex (LUBAC). 
These then go on to form the signaling complex I, which activates the 
nuclear factor kappa B (NF-κB) signaling pathway and promotes cell 
survival77. The overexpression of the IAP protein family has been reported 
to be associated with cancer development, with X-linked inhibitor of 
apoptosis protein (XIAP) classi ed as the most potent IAP family 
member78. The XIAP, cIAP1, and cIAP2 contain three baculovirus

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IAP repeat (BIR) domains, a ubiquitin-associated (UBA) domain, and a 
newly discovered gene (RING) nger motif, which exhibits ubiquitin E3 
ligase activity79. The IAPs prevent apoptosis by inhibiting downstream 
caspases, which are essential proteins of the apoptotic pathways. The 
cleaving of upstream caspases, such as caspase 8 and caspase 9, leads to the 
activation of downstream e ector caspases, such as caspase 3, eventually 
resulting in programmed cell  death76.

The most recently discovered IAP is the mammalian IAP ML-IAP, which 
is detectable in embryonic tissue, certain adult tissues and several cancer 
cell lines80. Although ML-IAP has only one BIR domain, it is reported to 
inhibit both the initiator caspase 9 and e ector caspases 3 and 7. Thus, it 
inhibits cell death induced through death receptors by overexpression of 
the cell death pathway proteins FADD, Bax, RIP, RIP3 and DR381. In 
fact, the most compelling evidence for the regulation of developmental cell 
death by IAPs originates from studies in Drosophila, in which loss of 
DIAP1 resulted in extensive early embryonic cell death and a 
corresponding increase in caspase activity82. However, these studies cannot 
be extrapolated to human models due to obvious anatomical and 
physiological di erences. An equivalent study in mammals is necessary to 
establish the role of these proteins in mammalian developmental cell death. 
Recent studies have greatly advanced our understanding of IAPs and their 
part in inhibiting cell death. Structurally, it is now evident how IAPs 
interact with caspases, and how this interaction can be regulated by IAP 
antagonists such as DIABLO. Though, further research is still required to 
de ne the various roles for di erent mammalian IAP proteins in the 
presence of cell-death stimuli. Indeed, there could potentially be some 
redundancy between family members. As a result, it is necessary to generate 
mice de cient for more than one IAP, to establish the role of IAPs in 
mammals. So far, researchers have only found one mammalian IAP 
antagonist, DIABLO. However, considering that there are three such 
proteins in Drosophila, other mammalian IAP antagonists must certainly 
exist. Future research investigating the direct interactions of BIR domains 
from these proteins with other cellular proteins are likely to illustrate the 
roles of IAP proteins in regulating cell death.

Conclusion
Apoptosis and necrosis are two of the most known types of cell death that 
play an essential role in cell development. The strictly distinct

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morphological features of apoptosis include chromosome condensation, 
nuclear fragmentation, and membrane blebbing. Necrosis, on the other 
hand, is characterized by the expansion of cellular organelles, plasma 
membrane rupture, and in ammatory responses resulting from the release 
of the intracellular contents. The apoptotic pathway — an 
energy-dependent cascade of molecular events — is initiated by 3 primary 
pathways: the extrinsic (cell-death) receptor pathway, the intrinsic 
(mitochondrial) pathway, and the stress-induced pathway in the 
endoplasmic reticulum. Although these pathways utilize di erent initiator 
caspases (caspase-8, caspase-9, and caspase-10, respectively), they activate 
the same downstream mediator molecule, caspase-3. Meanwhile, necrosis 
is classi ed as accidental cell death caused by internal or external stresses. In 
necrosis, the disruption of membrane homeostasis results in water 
imbalance between the extracellular and intracellular environments. 
Whether cells undergo apoptosis or necrosis depends on the availability of 
caspases, and intracellular ATP that determine the cell-death signal, 
signaling duration, tissue type, and the developmental stage of the tissue. 
In summary, necrosis is an unregulated and passive process that usually 
a ects a larger region of cells, whereas apoptosis is a contained and 
energy-dependent process that a ects an individual or smaller clusters of 
cells.

Studies have demonstrated that the repression of apoptosis, or the 
inhibition of programmed cell death, increases the possibility of 
malignancy. In contrast, uncontrolled apoptosis has been found to be 
associated with degenerative diseases such as acquired immunode ciency 
syndrome (AIDS), cancer, Parkinson's disease, and Alzheimer's disease. 
Recently, a programmed form of necrosis, necroptosis, has been proposed 
as an important pathway involved in many diseases. The primary function 
of necroptosis was believed to be infection control and protection against 
virus-induced apoptosis. However, like apoptosis, necroptosis has also 
been found to be associated with certain neurodegenerative diseases such as 
Alzheimer’s disease, multiple sclerosis, and amyotrophic lateral sclerosis. 
Due to the emerging crosstalk between the di ering forms of cell death, 
these processes are now considered interconnected. Thus, di erentiating 
between apoptotic, necrotic, and necroptotic cellular mechanisms is critical 
to understanding disease progression. The recent discovery of a family of 
genetically conserved proteins, known as IAPs, provided new insights into 
the molecules that play a critical role in mediating these cell death 
pathways. Inhibitors of apoptosis proteins (IAP) are a type of

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antiapoptotic protein involved in both, the intrinsic and extrinsic apoptotic 
pathways. Cellular IAP1 and 2 (cIAP1 and cIAP2) in particular, are the key 
molecules of the tumor necrosis factor α (TNFα) signaling pathway, which 
activates adaptor proteins such as TNF receptor-associated factor (TRAF), 
TNFR-associated death domain protein (TRADD), Receptor-interacting 
serine/threonine-protein kinase 1 (RIPK1), and linear ubiquitin chain 
assembly complex (LUBAC) to induce the NF-κB signaling pathway and 
promote cell survival. In short, the IAPs prevent apoptosis by inhibiting 
the normal functions of downstream caspases, including caspase 8, caspase 
9, and caspase 3. The impaired function of IAP could instruct the cells to 
undergo necroptosis or apoptosis instead of the NF-κB cell survival 
pathway. From this step of the cell death process, autoactivation of caspase 
8 would result in apoptosis whereas the absence of  caspase-8 
autoactivation would result in necroptosis.

Studies have demonstrated how the IAPs inhibit programmed cell death. 
However, further investigation is necessary to clarify the roles of di erent 
mammalian IAP proteins in the presence of various cell-death stimuli. 
Considering their newfound functions, continued research into the 
characteristics and mechanisms of IAP molecules will likely prove an 
e ective and viable approach to diagnosing or treating several elusive 
diseases.

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