DNAJA2 deficiency activates cGAS-STING pathway via the induction of aberrant mitosis and chromosome instability

Yaping Huang, Changzheng Lu, Hanzhi Wang, Liya Gu, Yang-Xin Fu () and Guo-Min Li ()
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Yaping Huang: University of Texas Southwestern Medical Center
Changzheng Lu: University of Texas Southwestern Medical Center
Hanzhi Wang: University of Texas Southwestern Medical Center
Liya Gu: University of Texas Southwestern Medical Center
Yang-Xin Fu: University of Texas Southwestern Medical Center
Guo-Min Li: University of Texas Southwestern Medical Center

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: Abstract Molecular chaperone HSP70s are attractive targets for cancer therapy, but their substrate broadness and functional non-specificity have limited their role in therapeutical success. Functioning as HSP70’s cochaperones, HSP40s determine the client specificity of HSP70s, and could be better targets for cancer therapy. Here we show that tumors defective in HSP40 member DNAJA2 are benefitted from immune-checkpoint blockade (ICB) therapy. Mechanistically, DNAJA2 maintains centrosome homeostasis by timely degrading key centriolar satellite proteins PCM1 and CEP290 via HSC70 chaperone-mediated autophagy (CMA). Tumor cells depleted of DNAJA2 or CMA factor LAMP2A exhibit elevated levels of centriolar satellite proteins, which causes aberrant mitosis characterized by abnormal spindles, chromosome missegregation and micronuclei formation. This activates the cGAS-STING pathway to enhance ICB therapy response in tumors derived from DNAJA2-deficient cells. Our study reveals a role for DNAJA2 to regulate mitotic division and chromosome stability and suggests DNAJA2 as a potential target to enhance cancer immunotherapy, thereby providing strategies to advance HSPs-based cancer therapy.

Date: 2023
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DOI: 10.1038/s41467-023-40952-0

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