Optineurin (OPTN) is a multifunctional, ubiquitin-binding adaptor protein which exhibits a high homology with IKBKG (NEMO, the regulatory subunit of the IkB kinase complex). OPTN has been implicated in regulating of various signaling pathways including NF-kappa-B activation, TBK1-mediated type I interferon production, programmed cell death and autophagy (reviewed in Markovinovic A et al. 2017; Slowicka K & van Loo G 2018; Toth RP & Atkin JD 2018). OPTN was identified as a negative regulator of tumor necrosis factor α (TNF-α)-induced signaling pathway by targeting several downstream components including receptor-interacting serine/threonine protein kinase 1 (RIPK1), caspase-8 (CASP8) and ubiquitin (Ub) carboxyl-terminal hydrolase CYLD (Zhu G et al. 2007; Nagabhushana A et al. 2011; Nakazawa S et al. 2016). TNF-α binding to TNF receptor 1 (TNFR1) results in the sequential formation of several signaling complexes to trigger inflammation, cell survival or cell death (Walczak H 2011; Ofengeim D & Yuan J 2013). The rapidly forming complex-I (TNFR1 signaling complex) is assembled at the receptor’s cytoplasmic tail. The components of this complex, including RIPK1, are rapidly conjugated with Ub chains by various E3 ligases (Micheau O and Tschopp J 2003; Yuan J et al. 2019). RIPK1 acts as rheostat in determining life or death decisions; K63-linked and M1-linked (linear) ubiquitination of RIPK1 stimulates inflammation and survival, whereas deubiquitination of RIPK1 promotes the formation of the cytosolic complex IIa, TRADD:TRAF2:RIPK1:FADD:caspase-8 (CASP8), which activates apoptosis (O’Donnell MA et al. 2007; Justus SJ and Ting AT 2015). Within the complex IIa, multiple procaspase-8 molecules interact via their tandem death-effector domains (DED), thereby facilitating both proximity-induced dimerization and proteolytic cleavage of procaspase-8, which are required for initiation of apoptotic cell death (Oberst A et al. 2010). When apoptosis is blocked, which occurs naturally in some cells or under certain pathophysiological conditions (e.g., expression of CASP8 inhibitory proteins such as CrmA and vICA after infection with cowpox virus or CMV and/or protein synthesis blockade that prevents NF-kappa-B-mediated expression of CASP8 and FADD-like apoptosis regulator (CFLAR, also known as c-FLIP)), deubiquitinated RIPK1 interacts with RIPK3 and MLKL to form the cytosolic complex IIb, which activates necroptosis (Ofengeim D et al. 2015; Yuan J et al. 2019). OPTN-knockout or OPTN-silenced HeLa cells exhibited enhanced cell death and cleavages of CASP8, CASP3, PARP, RIPK1 and CYLD in response to TNF-α + cycloheximide (CHX) (Nakazawa S et al. 2016). Co-immunoprecipitation (Co-IP) assays have revealed interactions between the endogenous procaspase-8 and OPTN in TNF-α +(CHX) -stimulated HeLa cells. Furthermore, co-IP has shown accelerated association of CASP8 with RIPK1 and FADD in OPTN-knockout HeLa cells upon stimulation with TNF-α +(CHX) treatment. When overexpressed in human embryonic kidney 293T (HEK293T) cells, OPTN associates with CASP8 at the DED, which is an essential domain for self-association and recruitment of other DED-containing proteins, such as FADD and CFLAR. These data suggest that OPTN downregulates apoptosis by binding to CASP8 (Nakazawa S et al. 2016).