2.2.4. LUBAC-Mediated Regulation of Cell Death

The TNFα-induced expression of NF-κB-target genes basically functions in anti-apoptosis. However, under conditions where the expression of NF-κB-target genes is suppressed, such as by the protein synthesis inhibitor cycloheximide, TNFα stimulation extensively induces apoptosis through the generation of TNFR complex IIa, which is composed of RIP1, FADD, and caspase 8 [55] (Figure 2). Subsequently, caspase 8 activates caspase 3 to induce extrinsic apoptosis, and the activated caspases cleave the N-terminal portion of HOIP [39,56]. A genetic deficiency of LUBAC subunits causes reduced expression of NF-κB genes, and thus e fficiently induces TNFα-mediated apoptosis in mice [11–13,38,57]. Characteristically, spontaneous *Sharpin*-deficient mice (*cpdm* mice) exhibit severe chronic proliferative dermatitis, and lack secondary lymphoid organs [58–60]. The combined genetic deletions of *Tnf* [11] or *Tnfr* [61] with *Sharpincpdm*/*cpdm* mice prevented the skin lesions, indicating that TNFα-mediated apoptosis plays a critical role in dermatitis in *Sharpin*-deficient mice. Importantly, the lack of secondary lymphoid organs, such as Peyer's patches, was not alleviated by the attenuation of TNF signaling. However, the genetic deletions of caspase 8 and Rip3k in mice (*Sharpincp<sup>d</sup>*/*cpdm*/*Casp8*+/−/*Rip3k*−/−) completely alleviated the phenotype [62]. Recently, Sharma and coworkers showed that the genetic ablation of *MyD88* in *Sharpin*-deficient *cpdm* mice (*Sharpincp<sup>d</sup>*/*cpdm*/*Myd88*−/−) completely and partially rescued the skin lesions and systemic inflammation, respectively [63]. Interestingly, they proposed that gu<sup>t</sup> microbiota may play a role in inflammation induction in *cpdm* mice. Therefore, LUBAC seems to be involved in the regulation of not only apoptosis, but also necroptosis.
