The carboxy-terminus of Hsp70-interacting protein (CHIP) is a ubiquitin ligase and co-chaperone belonging to Ubox family that plays a crucial role in the maintenance of cellular homeostasis by switching the equilibrium of the folding-refolding mechanism towards the proteasomal or lysosomal degradation pathway. It links molecular chaperones viz. HSC70, HSP70 and HSP90 with ubiquitin proteasome system (UPS), acting as a quality control system. CHIP contains charged domain in between N-terminal tetratricopeptide repeat (TPR) and C-terminal Ubox domain. TPR domain interacts with the aberrant client proteins via chaperones while Ubox domain facilitates the ubiquitin transfer to the client proteins for ubiquitination. Thus, CHIP is a classic molecule that executes ubiquitination for degradation of client proteins. Further, CHIP has been found to be indulged in cellular differentiation, proliferation, metastasis and tumorigenesis. Additionally, CHIP can play its dual role as a tumor suppressor as well as an oncogene in numerous malignancies, thus acting as a double agent. Here, in this review, we have reported almost all substrates of CHIP established till date and classified them according to the hallmarks of cancer. In addition, we discussed about its architectural alignment, tissue specific expression, sub-cellular localization, folding-refolding mechanisms of client proteins, E4 ligase activity, normal physiological roles, as well as involvement in various diseases and tumor biology. Further, we aim to discuss its importance in HSP90 inhibitors mediated cancer therapy. Thus, this report concludes that CHIP may be a promising and worthy drug target towards pharmaceutical industry for drug development.

Hsp70 相互作用蛋白 (CHIP) 的羧基末端是一种泛素连接酶和辅助伴侣，属于 Ubox 家族，通过将折叠-重折叠机制的平衡转向蛋白酶体或溶酶体，在维持细胞稳态中发挥着至关重要的作用降解途径。它连接分子伴侣，即。 HSC70、HSP70 和 HSP90 具有泛素蛋白酶体系统 (UPS)，充当质量控制系统。 CHIP 在 N 端四肽重复序列 (TPR) 和 C 端 Ubox 结构域之间包含带电结构域。 TPR 结构域通过分子伴侣与异常的客户蛋白相互作用，而 Ubox 结构域则促进泛素转移到客户蛋白上进行泛素化。因此，CHIP 是一种执行泛素化以降解客户蛋白的经典分子。此外，已发现CHIP参与细胞分化、增殖、转移和肿瘤发生。此外，CHIP 在多种恶性肿瘤中可以发挥肿瘤抑制基因和癌基因的双重作用，从而起到双重作用。在这篇综述中，我们报告了迄今为止建立的几乎所有 CHIP 底物，并根据癌症特征对它们进行了分类。此外，我们还讨论了其结构排列、组织特异性表达、亚细胞定位、客户蛋白的折叠-重折叠机制、E4连接酶活性、正常生理作用以及与各种疾病和肿瘤生物学的关系。此外，我们的目的是讨论其在 HSP90 抑制剂介导的癌症治疗中的重要性。因此，本报告得出的结论是，CHIP 可能是制药行业药物开发中一个有前途且有价值的药物靶标。