The linear ubiquitin chain assembly complex (LUBAC) is a RING between RING (RBR) E3 ligase complex composed of two E3 ubiquitin ligases HOIL-1L (RBCK1) and HOIP (RNF31) and an adaptor protein SHARPIN (Kirisako T et al. 2006; Walczak H et al. 2012; Rittinger K & Ikeda F 2017; Carvajal AR et al. 2021). The catalytic activity of LUBAC specifically generates Met1 (M1)-linked (also known as linear) polyubiquitin (polyUb) chains. The formation of mixed K63-/M1-linked heterotypic chains by LUBAC was also detected (Dittmar G & Winklhofer KF 2019; Carvajal AR et al. 2021). LUBAC regulates TNFα-induced TNFR1 signaling pathway through conjugating M1-linked polyUb to different components downstream of TNFR1 (Haas TL et al. 2009). CASP8 and FADD-like apoptosis regulator (CFLAR, also known as cellular FLICE-like inhibitory protein (cFLIP)) has been identified as the LUBAC substrate (Tang Y et la. 2018). RNF31 (HOIP), the catalytic subunit of LUBAC, co-immunoprecipitated with CFLAR (cFLIP) upon co-expression of tagged proteins in human embryonic kidney 293T (HEK293T) cells (Tang Y et la. 2018). The interaction between CFLAR and RNF31 and SHARPIN was detected in TNFα-induced HeLa cells stably expressing FLAG-CFLAR. Similarly, TNFα induced endogenous interaction between RNF31 and CFLAR in human immortalized T lymphocytes (Jurkat cells). Mutagenesis analysis revealed that the RBR domain of RNF31 and death effector domain 1 (DED1) of CFLAR (cFLIP) are critical for the RNF31:CFLAR interaction. Further, CFLAR was found to degrade faster in HOIP (RNF31)-deficient TNFα-induced HeLa cells (Tang Y et la. 2018). These data suggest that LUBAC binds CFLAR (cFLIP) to regulate CFLAR stability through M1-linked polyubiquitination of CFLAR (cFLIP(L)).