Goto Eiji, Tokunaga Fuminori
Department of Pathobiochemistry, Graduate School of Medicine, Osaka City University, Osaka 545-8585, Japan.
Department of Pathobiochemistry, Graduate School of Medicine, Osaka City University, Osaka 545-8585, Japan.
Biochem Biophys Res Commun. 2017 Mar 25;485(1):152-159. doi: 10.1016/j.bbrc.2017.02.040. Epub 2017 Feb 9.
NF-κB is crucial to regulate immune and inflammatory responses and cell survival. LUBAC generates a linear ubiquitin chain and activates NF-κB through ubiquitin ligase (E3) activity in the HOIP subunit. Here, we show that HOIP is predominantly cleaved by caspase at Asp390 upon apoptosis, and that is subjected to proteasomal degradation. We identified that FADD, as well as NEMO, is a substrate for LUBAC. Although the C-terminal fragment of HOIP retains NF-κB activity, linear ubiquitination of NEMO and FADD decreases upon apoptosis. Moreover, the N-terminal fragment of HOIP binds with deubiquitinases, such as OTULIN and CYLD-SPATA2. These results indicate that caspase-mediated cleavage of HOIP divides critical functional regions of HOIP, and that this regulates linear (de)ubiquitination of substrates upon apoptosis.
核因子κB（NF-κB）对调节免疫和炎症反应以及细胞存活至关重要。线性泛素链组装复合物（LUBAC）生成线性泛素链，并通过HOIP亚基中的泛素连接酶（E3）活性激活NF-κB。在此，我们表明，凋亡时HOIP主要在天冬氨酸390处被半胱天冬酶切割，并遭受蛋白酶体降解。我们确定，FADD以及核因子κB必需调节蛋白（NEMO）是LUBAC的底物。尽管HOIP的C末端片段保留NF-κB活性，但凋亡时NEMO和FADD的线性泛素化减少。此外，HOIP的N末端片段与去泛素酶，如OTULIN和CYLD-SPATA2结合。这些结果表明，半胱天冬酶介导的HOIP切割将HOIP的关键功能区域分开，并且这在凋亡时调节底物的线性（去）泛素化。
