PDF(Pubmed)
Abstract：
The anti-cancer target hRpn13 is a proteasome substrate receptor. However, hRpn13-targeting molecules do not impair its interaction with proteasomes or ubiquitin, suggesting other critical cellular activities. We find that hRpn13 depletion causes correlated proteomic and transcriptomic changes, with pronounced effects in myeloma cells for cytoskeletal and immune response proteins and bone-marrow-specific arginine deiminase PADI4. Moreover, a PROTAC against hRpn13 co-depletes PADI4, histone deacetylase HDAC8, and DNA methyltransferase MGMT. PADI4 binds and citrullinates hRpn13 and proteasomes, and proteasomes from PADI4-inhibited myeloma cells exhibit reduced peptidase activity. When off proteasomes, hRpn13 can bind HDAC8, and this interaction inhibits HDAC8 activity. Further linking hRpn13 to transcription, its loss reduces nuclear factor κB (NF-κB) transcription factor p50, which proteasomes generate by cleaving its precursor protein. NF-κB inhibition depletes hRpn13 interactors PADI4 and HDAC8. Altogether, we find that hRpn13 acts dually in protein degradation and expression and that proteasome constituency and, in turn, regulation varies by cell type.
摘要：
抗癌靶标hRpn13是蛋白酶体底物受体。然而,hRpn13靶向分子不会损害其与蛋白酶体或泛素的相互作用，提示其他关键细胞活动。我们发现hRpn13缺失导致相关的蛋白质组和转录组变化，在骨髓瘤细胞中对细胞骨架和免疫反应蛋白以及骨髓特异性精氨酸脱亚胺酶PADI4具有明显作用。此外，针对hRpn13的PROTAC共消耗PADI4、组蛋白脱乙酰酶HDAC8和DNA甲基转移酶MGMT。PADI4结合并瓜氨酸化hRpn13和蛋白酶体，来自PADI4抑制的骨髓瘤细胞的蛋白酶体表现出降低的肽酶活性。当关闭蛋白酶体时，hRpn13可以结合HDAC8,并且这种相互作用抑制HDAC8活性。进一步将hRpn13与转录联系起来，它的丢失会降低蛋白酶体通过切割其前体蛋白而产生的核因子κB（NF-κB）转录因子p50。NF-κB抑制耗尽hRpn13相互作用因子PADI4和HDAC8。总之,我们发现hRpn13在蛋白质降解和表达中双重作用，反过来,调节因细胞类型而异。
