Lim Yun Hwan, Park Yoon Jin, Lee Jieun, Kim Jung Hwa
Department of Biological Sciences, Inha University, Incheon, Korea.
Anim Cells Syst (Seoul). 2024 Feb 22;28(1):66-74. doi: 10.1080/19768354.2024.2321354. eCollection 2024.
C-terminal binding protein 1 (CtBP1) is a critical transcriptional corepressor of many tumor suppressor genes and plays diverse roles in the progression of cancers. The transcriptional repression function of CtBP1 is mediated by recruiting histone-modifying enzymes, such as histone deacetylases and histone methyltransferases, to target genes by binding with DNA-interacting factors. Several post-translational modifications of CtBP1 have been identified, including ubiquitination, phosphorylation, and SUMOylation. This paper reports that CtBP1 is conjugated by ISG15. Endogenous CtBP1 was modified by ISG15 after interferon-α treatment in HeLa cells. The ISGylation process of CtBP1 was regulated by deISGylation enzyme USP18 and ISG15 E3 ligase EFP. Interestingly, CtBP1 ISGylation affected the binding affinity between CtBP1 and some components of CtBP1-associated transcriptional complexes. HDAC1 and LSD1 bound more efficiently to ISG15-conjugated CtBP1 than non-conjugated CtBP1. On the other hand, binding between CtBP1 and HDAC4 was unaffected by ISG15 modification. Furthermore, ISG15 modification enhanced the transcriptional repression activity of CtBP1 on several target genes related to EMT and apoptosis. These findings suggest that the ISG15 modification of CtBP1 modulates the function and activity of CtBP1 and that CtBP1 ISGylation may provide a new insight for CtBP1-mediated cancers.
C末端结合蛋白1（CtBP1）是许多肿瘤抑制基因的关键转录共抑制因子，在癌症进展中发挥多种作用。CtBP1的转录抑制功能是通过与DNA相互作用因子结合，招募组蛋白修饰酶，如组蛋白去乙酰化酶和组蛋白甲基转移酶，作用于靶基因来介导的。已鉴定出CtBP1的几种翻译后修饰，包括泛素化、磷酸化和SUMO化。本文报道CtBP1被ISG15缀合。在HeLa细胞中，用α干扰素处理后，内源性CtBP1被ISG15修饰。CtBP1的ISGylation过程受去ISGylation酶USP18和ISG15 E3连接酶EFP的调节。有趣的是，CtBP1的ISGylation影响了CtBP1与CtBP1相关转录复合物的某些组分之间的结合亲和力。与未缀合的CtBP1相比，HDAC1和LSD1与ISG15缀合的CtBP1结合更有效。另一方面，CtBP1与HDAC4之间的结合不受ISG15修饰的影响。此外，ISG15修饰增强了CtBP1对与EMT和凋亡相关的几个靶基因的转录抑制活性。这些发现表明，CtBP1的ISG15修饰调节了CtBP1的功能和活性，并且CtBP1的ISGylation可能为CtBP1介导的癌症提供新的见解。
