Division of Radiation and Cancer Biology, Department of Radiation Oncology, University of Michigan, Ann Arbor, MI 48109, USA.
Department of Urology, the Second Affiliated Hospital, Third Military Medical University, Chongqing, PRC.
Mol Cell. 2018 Jun 21;70(6):1008-1024.e6. doi: 10.1016/j.molcel.2018.06.002.
UBE2M and UBE2F are two family members of neddylation E2 conjugating enzyme that, together with E3s, activate CRLs (Cullin-RING Ligases) by catalyzing cullin neddylation. However, whether and how two E2s cross-talk with each other are largely unknown. Here, we report that UBE2M is a stress-inducible gene subjected to cis-transactivation by HIF-1 and AP1, and MLN4924, a small molecule inhibitor of E1 NEDD8-activating enzyme (NAE), upregulates UBE2M via blocking degradation of HIF-1α and c-JUN. UBE2M is a dual E2 for targeted ubiquitylation and degradation of UBE2F, acting as a neddylation E2 to activate CUL3-Keap1 E3 under physiological conditions but as a ubiquitylation E2 for Parkin-DJ-1 E3 under stressed conditions. UBE2M-induced UBE2F degradation leads to CRL5 inactivation and subsequent NOXA accumulation to suppress the growth of lung cancer cells. Collectively, our study establishes a negative regulatory axis between two neddylation E2s with UBE2M ubiquitylating UBE2F, and two CRLs with CRL3 inactivating CRL5.
UBE2M 和 UBE2F 是 neddylation E2 连接酶家族的两个成员，它们与 E3 一起通过催化连接酶 cullin 的 neddylation 来激活 CRLs（Cullin-RING 连接酶）。然而，两个 E2 之间是否以及如何相互交流在很大程度上是未知的。在这里，我们报告 UBE2M 是一个应激诱导基因，受 HIF-1 和 AP1 的顺式-反式激活，以及 MLN4924，一种 E1 NEDD8-激活酶（NAE）的小分子抑制剂，通过阻断 HIF-1α 和 c-JUN 的降解来上调 UBE2M。UBE2M 是 UBE2F 的靶向泛素化和降解的双重 E2，作为 neddylation E2 在生理条件下激活 CUL3-Keap1 E3，但在应激条件下作为泛素化 E2 用于 Parkin-DJ-1 E3。UBE2M 诱导的 UBE2F 降解导致 CRL5 失活和随后的 NOXA 积累，从而抑制肺癌细胞的生长。总之，我们的研究建立了两个 neddylation E2 之间的负调节轴，UBE2M 泛素化 UBE2F，以及两个 CRL 之间的 CRL3 失活 CRL5。
