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Review
. 2021 Sep 1;9(6):1521-1555.
doi: 10.1016/j.gendis.2021.08.003. eCollection 2022 Nov.

Chaperone-assisted E3 ligase CHIP: A double agent in cancer

Sunny Kumar  1 , Malini Basu  2 , Mrinal K Ghosh  1
Affiliations
Review

Chaperone-assisted E3 ligase CHIP: A double agent in cancer

Sunny Kumar et al. Genes Dis. .

Abstract

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.

Keywords: CHIP; Chaperones (HSC70/HSP70 & HSP90); Oncogene; Therapy; Tumor suppressor; Ubiquitin proteasome system (UPS).

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Figures

Figure 1
Figure 1
Ubiquitin proteasome system (UPS). ATP mediated activation of free ubiquitin molecules occurs via binding of free ubiquitin to the ubiquitin binding enzyme (E1's) through a thioester linkage, subsequently the activated ubiquitin molecule gets transferred to ubiquitin conjugating enzymes (E2's). This Ub-E2's subsequently forms a complex with abnormal protein and with a specific E3 ubiquitin ligase enzyme which is responsible for transferring the ubiquitin moiety to the amino acid residue lysine present within the abnormal client protein that leads to poly-ubiquitination and 26S proteasome mediated degradation. Extensive role of E3 ubiquitin ligases as an E4 enzyme discovered recently as a new component of UPS is responsible for the elongation of ubiquitination chain. Finally, the ubiquitin molecules are recycled and again gets involved in next cycles of UPS.
Figure 2
Figure 2
Architectural alignment and subcellular localization of CHIP. (A) The schematic diagram represents the architectural alignment of all the three domains (TPR, Ubox and Charged) of CHIP. TPR (tetratricopeptide repeats) domain is present at the N-terminus of CHIP, while Ubox domain is at C-terminus. The charged domain is localized in between TPR and Ubox domains of CHIP. (B) The diagram represents the sub-cellular localization of CHIP in endoplasmic reticulum (ER), mitochondria, cytoplasm, nucleus and golgi bodies.
Figure 3
Figure 3
Molecular chaperones (HSP70/HSC70 and HSP90) dependent, independent and direct mechanisms of CHIP mediated degradation of client proteins. CHIP mediated degradation of client proteins through inhibition of either (A) HSP70/HSC70 mediated refolding; (B) HSP90 mediated refolding or, (C) Chaperones independent route for degradation of client proteins. Arrows indicate either positive (solid) or negative (T shaped) regulation.
Figure 4
Figure 4
Timeline for client proteins of CHIP. The figure depict the timeline of all documented client proteins of CHIP identified till December 2020.
Figure 5
Figure 5
Pie-in-pie chart of CHIP as a double agent in the context to cancer. CHIP client proteins classified according to the hallmarks of cancer and its dual role as a tumor suppressor (left hand sided pie chart) and as an oncogene (right hand sided pie chart) explained.
Figure 6
Figure 6
Chemical structures of HSP90 inhibitors. Figure depicts the chemical structures of various HSP90 inhibitors viz., geldanamycin, 17AAG, 17DMAG, IPI-504, AT13387, AUY922, SNX5422, STA9090, XL888, CUDC 305, BIIB021, KW-2478 and TAS-116, act as anti-cancer agents. All the structures were drawn by using chem draw software.
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