2.2.2. LUBAC in Acquired Immune Responses

The NF-κB activity plays important roles in lymphocyte development and antigen receptor-mediated acquired immune responses in mammals [33]. Characteristically, a protein complex composed of CARMA1, BCL10, and MALT1 (CBM complex) is critical to activate the B cell receptor (BCR)- and T cell receptor (TCR)-mediated NF-κB activation pathways [45]. In mice B cells, LUBAC has no influence on the IgM-induced BCR pathway, whereas the LUBAC activity is critical for the

CD40-mediated NF-κB activation pathway and B1 cell development [34]. In contrast, in T cells, LUBAC is involved in the TCR-mediated NF-κB activation pathway, FOXP3+ regulatory T cell (Treg) development, and homeostasis [46]. In the course of the TCR pathway, HOIL-1L is cleaved at Arg165-Gly166 by MALT1, a paracaspase [47]. Moreover, BCL10 is linearly ubiquitinated by LUBAC [48]. However, the importance of the E3 activity of LUBAC in the antigen receptor-mediated NF-κB activation pathway remains to be established [49]. Therefore, further studies are necessary to clarify the function of LUBAC in the antigen receptor-mediated NF-κB activation pathways in lymphocytes.

### 2.2.3. LUBAC in the Genotoxic Stress Response and Inflammasome Activation

DNA damaging anti-cancer agents, such as camptothecin, etoposide, and doxorubicin, stimulate the NF-κB pathway through the activation of ataxia telangiectasia mutated (ATM) kinase and various post-translational modifications of NEMO, such as phosphorylation, SUMOylation, and ubiquitination [50]. In the genotoxic stress-induced NF-κB activation pathway, X-linked inhibitor of apoptosis (XIAP) conjugates K63-ubiquitin chains to ELKS, which then induces the LUBAC-mediated linear ubiquitination of NEMO in the cytosol [51]. Similarly, the XIAP-mediated K63-linked ubiquitination of RIP2 recruits LUBAC to activate the NOD2-mediated NF-κB activation pathway [52], which plays an important role in the bacterial peptidoglycan-mediated innate immune response.

The inflammasome is a protein complex that activates pro-inflammatory cytokines, such as pro-IL-1β and pro-IL-18. Upon stimulation through Toll-like receptors (TLRs) by damage-associated molecular patterns (DAMPs) and PAMPs, inflammasomes become oligomerized and activate caspase 1. The ubiquitin system functions as both a negative and positive regulator of inflammasomes [53]. The nucleotide binding and leucine-rich repeat-containing protein 3 (NLRP3) is one of the best characterized inflammasomes. LUBAC conjugates a linear ubiquitin chain to the caspase-recruit domain (CARD) of the ASC component, and activates the NLRP3 inflammasome in macrophages [54].
