Apoptosis

Caspases are typically known for their role in cell death. However some caspases have recently been investigated for their function during cell proliferation and differentiation. Of these caspase-14 shows a unique expression pattern in the skin and appears to be involved in keratinocyte differentiation. Procaspase-14 is detected in the stratifying epithelium while activated caspase-14 is found only in terminally differentiated keratinocytes (1). Caspase-14 activity is not involved in apoptosis. Instead, caspase-14 is important for keratinization of the epithelium.

FAS-associated death domain protein (FADD) is a 23 kDa adaptor protein involved in initiating apoptosis. FADD is best known for its involvement in extrinsic/death receptor-mediated apoptosis, but it is also involved in initiating necroptosis with serine/threonine kinases RIPK1 and RIPK3 (1). FADD binds to receptors of the tumor necrosis factor (TNF) superfamily through its C-terminal death domain (DD). During extrinsic apoptosis, binding of the Fas-ligand causes trimerization of the Fas-receptor which then binds to FADD via the DD domain.

Aside from their important role in apoptosis, caspases also play an important role in inflammatory processes. Humans express four inflammatory caspases: Caspase-1, -4, -5, and -12. Caspase-12 is a 48 kDa protein localized to the ER and involved in the ER stress response. Caspase-12 contains a caspase-associated recruitment domain (CARD) and two catalytic domains, p20 and p10 (1).

While known for their role in programmed cell death, caspases are also essential for mediating inflammatory responses and innate immunity. Binding of microbial molecules by pattern recognition receptors triggers the formation of the multiprotein inflammasome complex and the activation of caspase-1 (1). Caspase-1 is then able to mediate the activation and secretion of proinflammatory cytokines including interleukin-1. In addition to caspase-1, caspase-11 also plays an important role during the inflammatory response.

The 78 kDa glucose-regulated protein (GRP78) is the eukaryotic orthologue to the prokaryotic heat shock 70 kDa protein 5 (HSPA5). GRP78 is also sometimes referred to as BiP. GRP78 is a member of the HSP70 family and plays dynamic roles in protein regulation within the endoplasmic reticulum. GRP78 is the most abundant chaperone in the ER and plays an important role in regulating the unfolded protein response (UPR) (1). GRP78 forms a multiprotein chaperone complex with DNAJB11, HSP90B1, HYOU, PDIA2, PDIA4, PDIA6, PPIB, SDF2L1, UGT1A1, and ERP29.

The mammalian forkhead O class transcription factors (FOXO) regulate diverse cellular processes such as metabolism, cell cycle, and apoptosis. Activity of these transcription factors can be regulated by diverse post-translational modifications including phosphorylation, acetylation, and ubiquitination (1). These modifications can alter nuclear transport, DNA binding, and protein-protein interactions to alter transcriptional activity. The best studied member of the FOXO family is FOXO1.

Caspase-2 is a highly conserved member of the caspase family involved in the initiation and execution of apoptosis. While its function is still poorly understood, caspase-2 is thought to be important for apoptosis in response to DNA damage, bacterial infection, or abnormal mitosis (1). Caspase-2 contains an N-terminal caspase recruitment domain, the large p19 subunit containing the active site, and the small C-terminal p12 subunit (1). In response to various apoptotic signals caspase-2 undergoes dimerization.

VPS34, vacuolar protein sorting 34, is the only identified Class III phosphoinositide-3 kinase (PI3K) in mammals and is ubiquitously expressed in all eukaryotic cells. VPS34 is a 100 kDa protein responsible for phosphorylating phosphatidylinositol to produce phosphatidylinositol 3-phosphate (PI3P). PI3P is an important intermediate in the development of the double-membraned autophagosome during autophagy, indicating a role for VPS34 in autophagy initiation. PI3P allows VPS34 to form complexes with ATG14L during the elongation of the autophagosome membrane.

C/EBP homologous protein (CHOP) is a transcription factor that regulates apoptosis in response to cellular stress. CHOP also known as growth arrest and DNA damage 153 (GADD153) was first cloned because of its induction in response to genotoxic stress such as UV irradiation. CHOP has now been shown to be induced mainly by ER-stress (1). CHOP is normally expressed at low levels and localizes to the cytoplasm. Cellular stress triggers an upregulation of CHOP levels and accumulation in the nucleus where it can act as either a transcriptional repressor or activator (1).

Cellular inhibitor of apoptosis protein-1 (cIAP-1) is an anti-apoptotic protein that is able to bind to caspases and inhibit their activity. Additionally cIAP-1 contains a RING domain with E3 ubiquitin ligase activity that is able to mediate the regulation of NF-kB signaling through the ubiquitination and degradation of various substrate proteins. Depending on cellular context, the RING domain of cIAP-1 can either promote or inhibit apoptosis.