Cullin-RING ligase 5 (CRL5) is a multi-protein complex and consists of a scaffold protien cullin 5, a RING protein RBX2 (also known as ROC2 or SAG), adaptor proteins Elongin B/C, and a substrate receptor protein SOCS. Through targeting a variety of substrates for proteasomal degradation or modulating various protein-protein interactions, CRL5 is involved in regulation of many biological processes, such as cytokine signal transduction, inflammation, viral infection, and oncogenesis. As many substrates of CRL5 are well-known oncoproteins or tumor suppressors, abnormal regulation of CRL5 is commonly found in human cancers. In this review, we first briefly introduce each of CRL5 components, and then discuss the biological processes regulated by four members of SOCS-box-containing substrate receptor family through substrate degradation. We next describe how CRL5 is hijacked by a variety of viral proteins to degrade host anti-viral proteins, which facilitates virus infection. We further discuss the regulation of CUL5 and its various roles in human cancers, acting as either a tumor suppressor or an oncoprotein in a context-dependent manner. Finally, we propose novel insights for future perspectives on the validation of cullin5 and other CRL5 components as potential targets, and possible targeting strategies to discover CRL5 inhibitors for anti-cancer and anti-virus therapies.

Cullin-RING 连接酶 5 (CRL5) 是一种多蛋白复合物，由支架蛋白 cullin 5、RING 蛋白 RBX2（也称为 ROC2 或 SAG）、衔接蛋白 Elongin B/C 和底物受体蛋白 SOCS 组成。通过针对蛋白酶体降解的各种底物或调节各种蛋白质-蛋白质相互作用，CRL5 参与许多生物过程的调节，如细胞因子信号转导、炎症、病毒感染和肿瘤发生。由于 CRL5 的许多底物是众所周知的癌蛋白或肿瘤抑制因子，CRL5 的异常调节在人类癌症中很常见。在这篇综述中，我们首先简要介绍了每个 CRL5 成分，然后讨论了四个含有 SOCS-box 的底物受体家族成员通过底物降解调控的生物过程。我们接下来描述 CRL5 如何被各种病毒蛋白劫持以降解宿主抗病毒蛋白，从而促进病毒感染。我们进一步讨论了 CUL5 的调节及其在人类癌症中的各种作用，以上下文相关的方式充当肿瘤抑制因子或癌蛋白。最后，我们为验证 cullin5 和其他 CRL5 成分作为潜在靶标的未来前景提出了新的见解，以及发现用于抗癌和抗病毒治疗的 CRL5 抑制剂的可能靶向策略。