Cell and Chemical Biology, Leiden University Medical Center, Leiden, The Netherlands.
Nat Commun. 2019 Sep 4;10(1):3987. doi: 10.1038/s41467-019-11773-x.
In contrast to our extensive knowledge on ubiquitin polymer signaling, we are severely limited in our understanding of poly-SUMO signaling. We set out to identify substrates conjugated to SUMO polymers, using knockdown of the poly-SUMO2/3 protease SENP6. We identify over 180 SENP6 regulated proteins that represent highly interconnected functional groups of proteins including the constitutive centromere-associated network (CCAN), the CENP-A loading factors Mis18BP1 and Mis18A and DNA damage response factors. Our results indicate a striking protein group de-modification by SENP6. SENP6 deficient cells are severely compromised for proliferation, accumulate in G2/M and frequently form micronuclei. Accumulation of CENP-T, CENP-W and CENP-A to centromeres is impaired in the absence of SENP6. Surprisingly, the increase of SUMO chains does not lead to ubiquitin-dependent proteasomal degradation of the CCAN subunits. Our results indicate that SUMO polymers can act in a proteolysis-independent manner and consequently, have a more diverse signaling function than previously expected.
与我们对泛素聚合物信号的广泛了解相比，我们对聚 SUMO 信号的理解还非常有限。我们着手使用多聚 SUMO2/3 蛋白酶 SENP6 的敲低来鉴定与 SUMO 聚合物连接的底物。我们鉴定了超过 180 个受 SENP6 调节的蛋白质，这些蛋白质代表了高度相互关联的蛋白质功能组，包括组成性着丝粒相关网络（CCAN）、CENP-A 加载因子 Mis18BP1 和 Mis18A 以及 DNA 损伤反应因子。我们的结果表明 SENP6 对蛋白质组具有显著的去修饰作用。缺乏 SENP6 的细胞增殖严重受损，在 G2/M 期积累，并经常形成微核。在缺乏 SENP6 的情况下，CENP-T、CENP-W 和 CENP-A 向着丝粒的积累受损。令人惊讶的是，SUMO 链的增加并不会导致 CCAN 亚基的泛素依赖性蛋白酶体降解。我们的结果表明，SUMO 聚合物可以以一种不依赖于蛋白水解的方式发挥作用，因此，其信号功能比之前预期的更加多样化。
