DNAJA2 deficiency activates cGAS-STING pathway via the induction of aberrant mitosis and chromosome instability
© 2023. Springer Nature Limited..
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.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2023 |
|---|---|
| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:14 |
|---|---|
| Enthalten in: |
Nature communications - 14(2023), 1 vom: 28. Aug., Seite 5246 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Huang, Yaping [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
Chromogranin A |
|---|
| Anmerkungen: |
Date Completed 31.08.2023 Date Revised 19.11.2023 published: Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1038/s41467-023-40952-0 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM361387067 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM361387067 | ||
| 003 | DE-627 | ||
| 005 | 20231226085029.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231226s2023 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1038/s41467-023-40952-0 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1204.xml |
| 035 | |a (DE-627)NLM361387067 | ||
| 035 | |a (NLM)37640708 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Huang, Yaping |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a DNAJA2 deficiency activates cGAS-STING pathway via the induction of aberrant mitosis and chromosome instability |
| 264 | 1 | |c 2023 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 31.08.2023 | ||
| 500 | |a Date Revised 19.11.2023 | ||
| 500 | |a published: Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2023. Springer Nature Limited. | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a Chromogranin A |2 NLM | |
| 650 | 7 | |a Nucleotidyltransferases |2 NLM | |
| 650 | 7 | |a EC 2.7.7.- |2 NLM | |
| 650 | 7 | |a HSP70 Heat-Shock Proteins |2 NLM | |
| 650 | 7 | |a DNAJA2 protein, human |2 NLM | |
| 650 | 7 | |a HSP40 Heat-Shock Proteins |2 NLM | |
| 700 | 1 | |a Lu, Changzheng |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Hanzhi |e verfasserin |4 aut | |
| 700 | 1 | |a Gu, Liya |e verfasserin |4 aut | |
| 700 | 1 | |a Fu, Yang-Xin |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Guo-Min |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Nature communications |d 2010 |g 14(2023), 1 vom: 28. Aug., Seite 5246 |w (DE-627)NLM199274525 |x 2041-1723 |7 nnns |
| 773 | 1 | 8 | |g volume:14 |g year:2023 |g number:1 |g day:28 |g month:08 |g pages:5246 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1038/s41467-023-40952-0 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 14 |j 2023 |e 1 |b 28 |c 08 |h 5246 | ||