CD317 maintains proteostasis and cell survival in response to proteasome inhibitors by targeting calnexin for RACK1-mediated autophagic degradation.

Abstract

Unbalanced protein homeostasis (proteostasis) networks are frequently linked to tumorigenesis, making cancer cells more susceptible to treatments that target proteostasis regulators. Proteasome inhibition is the first licensed proteostasis-targeting therapeutic strategy, and has been proven effective in hematological malignancy patients. However, drug resistance almost inevitably develops, pressing for a better understanding of the mechanisms that preserve proteostasis in tumor cells. Here we report that CD317, a tumor-targeting antigen with a unique topology, was upregulated in hematological malignancies and preserved proteostasis and cell viability in response to proteasome inhibitors (PIs). Knocking down CD317 lowered Ca2+ levels in the endoplasmic reticulum (ER), promoting PIs-induced proteostasis failure and cell death. Mechanistically, CD317 interacted with calnexin (CNX), an ER chaperone protein that limits calcium refilling via the Ca2+ pump SERCA, thereby subjecting CNX to RACK1-mediated autophagic degradation. As a result, CD317 decreased the level of CNX protein, coordinating Ca2+ uptake and thus favoring protein folding and quality control in the ER lumen. Our findings reveal a previously unrecognized role of CD317 in proteostasis control and imply that CD317 could be a promising target for resolving PIs resistance in the clinic.

• Authors: Jian Cheng, Guizhong Zhang, Tian Deng, Zhao Liu, Mengqi Zhang, Pengchao Zhang, Funmilayo O Adeshakin, Xiangyun Niu, Dehong Yan, Xiaochun Wan, Guang Yu
• Journal: Cell death & disease (Cell Death Dis) Vol. 14 Issue 5 Pg. 333 (05 20 2023) ISSN: 2041-4889 [Electronic] England
• PMID: 37210387 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2023. The Author(s).

Chemical References

• Calnexin
• Molecular Chaperones
• Neoplasm Proteins
• Proteasome Inhibitors
• RACK1 protein, human
• Receptors for Activated C Kinase
• BST2 protein, human
• Bone Marrow Stromal Antigen 2

Topics

• Humans
• Calnexin (metabolism)
• Cell Survival
• Molecular Chaperones (metabolism)
• Neoplasm Proteins (genetics, metabolism)
• Proteasome Inhibitors (pharmacology)
• Proteostasis
• Receptors for Activated C Kinase (genetics, metabolism)
• Bone Marrow Stromal Antigen 2 (genetics, metabolism)