Primarily, cIAP1 was discovered by its involvement in inflammation/apoptosis signaling interacting with tumor necrosis factor receptor-2 associated factors (TNFR2-TRAFs) via its N-terminal BIR domain [29]. The major biological activities of cIAP1 cover a positive regulation of the canonical transcription factor nuclear factor kappaB (NF-κB) activation pathways. By this, cIAP1 complexes with TRAF2, Src homology 2 domain-containing protein tyrosine phosphatase 1 (SHP1), Src and myeloid differentiation primary response 88 (MyD88) to promote canonical activation of NF-κB [30]. Briefly, in the TNFR1 complex, cIAP1/2 serve as ubiquitin ligases for receptor-interacting serine/threonine-protein kinase 1 (RIPK1), which is needed for TNF-α mediated NF-κB and mitogen-activated protein kinase (MAPK) signaling, gene expression, differentiation, mitosis and inhibition of both, caspase-dependent and -independent cell death. In addition, cIAP1/2 limit the non-canonical NF-κB activation pathway. Here, cIAP1/2 act as ubiquitin ligases that target NF-κB-inducing kinase (NIK) for degradation. Further, upon viral infection, cIAP1/2 ubiquitinate TRAF3/6 which is an essential factor for NF-κB deregulation, while attenuation of cIAP1/2 impedes an antiviral response via inhibition of the virus-triggered activation of NF-κB, interferon regulatory factor 3 (IRF3) and interferon-beta (IFN-β) induction [31].

The expression level of cIAP1 is regulated by a variety of transcriptional and post-translational mechanisms including microRNAs (miRNAs) and proteasomal degradation. For instance, microRNA-29c (miR-29c) binds to the 3′-UTR of cIAP1 effectively downregulating its mRNA and protein levels [32]. Further, downregulation of ubiquitin thioesterase OTU domain ubiquitin aldehyde binding 1 (OTUB1) enhances the degradation of cIAP1 and inhibits the TNF-related weak inducer of apoptosis (TWEAK)-induced MAPK and NF-κB pathway [33]. Upon genotoxic stress, a bilateral cell death regulation involving the ripoptosome (RIP1/3-FADD-Caspase-8-c-FLIP) complex is reported: cIAP1 and cIAP2 directly ubiquitinate RIP1 which associates with the pro-survival transforming growth factor beta-activated kinase 1 (TAK1) and triggers proteolytic degradation of the ripoptosome complex while attenuation of IAPs allows the proper formation of the complex [34].

Beside its function in concert with cIAP1, cIAP2 is involved in response to metal stress, DNA repair and together with XIAP and Survivin in exosomal secretion ^[35][36][37][35,36,37]. The latter may not only serve as warning signals, but may also play a role in providing protection to the cancer cells against potential dangers in the tumor microenvironment [38].

As a response to histone deacetylase (HDAC) inhibitor Panobinostat treatment, cIAP2 exhibits the highest upregulation in line with a decreased level of DNA double-strand break (DSB) repair protein meiotic recombination 11 homolog (MRE11). Moreover, cIAP2 directly interacts with MRE11, promotes its ubiquitination and directs it to degradation that in turn delays DNA DSB repair resulting in increased radiation sensitivity [35].

Human XIAP was initially discovered as an IAP-like apoptosis inhibitor protein by its homology to baculovirus IAP genes [39]. XIAP is an archetypical IAP protein that, in contrast to other family members, inhibits the active catalytic sites of caspases-3 and caspases-7 in a direct manner and interferes with the dimerization and activation of caspase-9. This prevents their downstream effector functions, including the release of mitochondrial IAP antagonists such as second mitochondrial activator of caspases (SMAC/Diablo) and the serine peptidase HtrA2/Omi, that bind XIAP’s BIR domains, releasing active caspases into the cytosol [40]. In addition, recent studies presented XIAP as a multifunctional protein involved in cellular and metabolic regulatory circuits such as invasion, migration, necroptosis, oxidative stress, inflammasome formation and autophagy ^{[41][42][43][44][45][46][47][48][49][50]}[41,42,43,44,45,46,47,48,49,50]. XIAP´s BIR domain 1 mediates activation of stress-responsive signaling pathways, such as Jun Kinase (JNK) [51] and MAPK phosphorylation cascade that in turn activate NF-κB. XIAP also activates NF-κB by promoting the translocation of the p65 subunit to the nucleus and by degradation of the NF-κB inhibitor IκB [52]. XIAP empowers interleukin-17 mediated NF-κB activation and caspase-3 inhibition that drives colon tumor formation [44]. In line with Survivin, XIAP represents a radiation resistance factor and attenuation of the protein triggers radiation response in CRC cancer cell lines ^[53][54][53,54].

Survivin is among the most studied members of the IAP family. The protein was discovered in the late nineties as its smallest member involved in fetal development and cancer progression. Survivin is downregulated in most terminally differentiated cells and re-expressed in the majority of solid and liquid human tumors investigated ^[55][56][55,56]. Survivin is a prime example of a multifunctional protein involved in a variety of regulatory circuits in tumor cells ^[37][57][37,57]. By this, a present conception is that most IAPs, except for XIAP, block apoptosis by mechanisms other than direct caspase inhibition [58], but via cooperative interactions with other partners. Thus, an association of Survivin with hepatitis B X-interacting protein (HBXIP) and/or XIAP inhibits caspases, while binding to SMAC/Diablo counteracts this activity. Moreover, Survivin is expressed in a cell cycle regulated manner participating in cell division as an interactor of chromosomal passenger complex (CPC) proteins INCENP, Borealin and Aurora-B ^[59][60][59,60]. In malignant cells, however, Survivin is regulated independently of mitosis by a variety of oncogenic pathways. Further, Survivin is a predominantly nucleocytoplasmic protein; however, shuttling to or from other compartments like the nucleus is mediated by Exportin-1, irradiation and post-translational regulations such as homodimerization and acetylation of residue K129 ^[61][62][61,62]. Survivin is subjected to multiple post-translational modifications that mostly are decision-makers on its functions and fate of the host. For instance, phosphorylation of residue T34 by p34(cdc2)-cyclin B1 facilitates proper Survivin-caspase-9 interaction that results in inhibition of apoptosis [63]. In addition, Survivin is a radiation-inducible factor mediating the cellular radiation response in a multitude of tumors including colorectal cancer ^[64][65][66][64,65,66]. By this, Survivin accumulates in the nucleus and interacts with a prime non-homologous end joining repair factor DNA-dependent protein kinase (DNA-PKcs) ^[67][68][67,68]. Survivin forms a heterotetramer complex with DNA-PKcs that results in a conformational change on the DNA-PKcs phosphoinositide 3-kinase domain with enhanced enzymatic activity and detection of differentially abundant phosphopeptides and proteins implicated in the DNA damage response [69].

With a molecular weight of 528 kDa, BRUCE/Apollon is a huge E3 ubiquitin transferase whose mutation causes embryonic lethality ^[70][71][70,71]. In concert with other IAPs, one of the main functions of BRUCE is inhibition of apoptosis [70]. BRUCE binds and ubiquitinates SMAC/Diablo, caspase-9 and mitochondrial serine peptidase HtrA2/Omi to prevent apoptosis by facilitating their proteasomal degradation ^[72][73][72,73]. Early in mitosis, BRUCE binds the anaphase-promoting complex/cyclosome (APC/C) and enables the degradation of Cyclin A by ubiquitination independent of cyclin-dependent kinases (CDKs) [74]. However, in the late phase of cytokinesis, BRUCE is an essential component of the midbody ring and the tubular recycling system under the regulation of mitotic kinesin-like protein-1 to regulate cytokinetic abscission [75]. Upon DNA damage, BRUCE acts as a scaffold to form a complex with ubiquitin-specific peptidase 8 (USP8) and breast cancer susceptibility gene C terminus-repeat inhibitor of human telomerase repeat transcriptase expression-1 (BRIT1) at the DSBs, which is vital for the formation of BRIT1 DNA damage foci [76]. BRUCE further regulates ATR-directed signaling pathways in DNA replication stress via interaction with pre-mRNA-processing factor 19, while depletion of BRUCE causes a stalled DNA replication, prevents the activation of ATR and inhibits the phosphorylation of CHK1 and replication protein A [77].

LIVIN (37/39 kDa) plays a key role in a multitude of cellular mechanisms and stress responses including radiation response, invasion, hypoxia-resistance and autophagy ^{[78][79][80][81][82]}[78,79,80,81,82]. LIVIN inhibits apoptosis by binding both, caspase-3/7 as well as TNFα-induced DEVD-like caspase. In addition, LIVIN indirectly inhibits caspase-9 via apoptotic protease activating factor-1 (Apaf-1) [83]. However, reports on a bidirectional regulation between caspases and LIVIN revealed that the truncation of LIVIN (28/30 kDa) by caspase-3/7 transforms it to a pro-apoptotic protein ^[84][85][84,85]. Chemosensitivity studies in colon cancer cells further revealed LIVIN as a drug resistance gene against etoposide (VP-16) and 5-fluorouracil (5-FU) [86], while attenuation of the protein significantly decreases the size of colon cancer xenograft tumors ^[86][87][86,87]. Upon irradiation, LIVIN overexpression is associated with cellular radioresistance, whereas attenuation of LIVIN decreases radiation-induced cell invasion ability and enhances radiation response ^[78][79][78,79].

NAIP was first discovered as spinal muscular atrophy (SMA) related gene whose deletion or mutation was restricted to SMA patients [88]. However, comprehensive studies over the last years indicate the relevance of NAIP in a variety of different molecular mechanisms and diseases such as cytokinesis, inflammasome formation, amyloid-β toxicity, amyotrophic lateral sclerosis (ALS) and Parkinson’s disease ^{[89][90][91][92][93]}[89,90,91,92,93]. The least-studied member of IAP family, hILP-2 is discovered as a protein owing a high sequence homology to XIAP but no inhibitory effect on TNF-mediated apoptosis. Nevertheless, it can inhibit Bcl-2-associated X protein (Bax) or caspase-9 and Apaf-1 triggered apoptosis. Moreover, hILP-2 directly interacts with cleaved caspase-9 [94] and attenuation of hILP-2 triggers apoptosis and inhibits migration [95].