Human cytomegalovirus (HCMV) encodes several viral cell death inhibitors that target different key regulators of the extrinsic and intrinsic apoptotic pathways. Viral inhibitor of caspase-8 activation (vICA) protein encoded by the UL36 gene suppresses the extrinsic apoptotic signaling pathway by binding to the prodomain of caspase-8 (CASP8) and preventing its activation (Skaletskaya A et al. 2001; McCormick et al, 2010; Fliss PM & Brune W 2012).

During infection in human cells, herpes simplex virus (HSV)-1 and HSV-2 modulate cell death pathways using the large subunit (R1) of viral ribonucleotide reductase (RIR1 or UL39) (Dufour F et al. 2011; Guo H et al. 2015; Yu X et al. 2016; Ali M et al.2019). The N-terminal region of RIR1 protein carrying the RIP homotypic interaction motif (RHIM)-like element is sufficient for RHIM-dependent interaction with receptor‐interacting protein kinase 1 (RIPK1) and receptor‐interacting protein kinase 3 (RIPK3) thus inhibiting the interaction between RIPK1 and RIPK3 (Guo H et al. 2015; Yu X et al. 2015). An intact RHIM is required for the interaction between RIPK1 and RIPK3 that occurs downstream of tumour necrosis factor receptor 1 (TNFR1) activation during the programmed cell death response known as necroptosis (Sun X et al. 2002). In addition, the large carboxyl-terminal region of HSV RIR1 protein mediates the binding to caspase 8 (CASP8) (Dufour F et al. 2011; Guo H et al. 2015). HSV RIR1 is thought to block necroptosis in infected human cells by interactions with RIPK1, RIPK3 and CASP8 (Guo H et al. 2015; Mocarski ES et al. 2015).

Caspase-8 (CASP8) and caspase-10 (CASP10) are involved in RIG-I/MDA5-dependent antiviral immune responses. Caspase-8/10 activation contributes to NF-kB activation in response to viral dsRNA.
Caspase-8/10 are synthesized as zymogens (procaspases), containing a large N-terminal prodomain with two death effector domains (DED), and a C-terminal catalytic subunit composed of small and a large domain separated by a smaller linker region. FADD plays a crucial role in the recruitment and activation of procaspase-8/10. The two DED domains of procaspase-8/10 interacts with DED domain of FADD.

The short form of cellular FLIP (FLIP(S) or c-FLIPS) has two death effector domains DEDs, which can bind to FADD and caspase-8 (CASP8). FLIP(S) protects the cells from apoptosis by inhibiting the processing of caspase-8 at the receptor level (Scaffidi C et al. 1999; Micheau O et al 2001).

FLIP(S) is a short-lived protein which is sensitive to ubiquitination and proteasomal degradation (Poukkula M et al. 2005). Protein kinase C (PKC)- mediated phosphorylation of FLIP(S) at Ser193 was shown to prolongs the half-life of FLIP(S) by inhibiting its polyubiquitination (Kaunisto A et al. 2009).