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

Yaping Huang1, Changzheng Lu2,3, Hanzhi Wang1

  • 1Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA.

Nature Communications
|August 28, 2023
PubMed

Insights

Tumors lacking DNAJA2 show improved responses to immune-checkpoint blockade (ICB) therapy. DNAJA2 deficiency disrupts mitosis, activating pathways that enhance cancer immunotherapy effectiveness.

Area of Science:

  • Oncology
  • Molecular Biology
  • Immunology

Background:

  • Molecular chaperones like HSP70s are cancer therapy targets, but their broadness limits efficacy.
  • HSP40 cochaperones, such as DNAJA2, offer client specificity and could be superior therapeutic targets.

Purpose of the Study:

  • To investigate the role of DNAJA2 in cancer, particularly its impact on immune-checkpoint blockade (ICB) therapy response.
  • To elucidate the molecular mechanisms by which DNAJA2 influences tumor cell biology and immune interactions.

Main Methods:

  • Analysis of tumors with DNAJA2 deficiency and their response to ICB therapy.
  • Investigating the role of DNAJA2 in maintaining centrosome homeostasis via chaperone-mediated autophagy (CMA).
  • Assessing the impact of DNAJA2 depletion on mitotic division, chromosome stability, and the cGAS-STING pathway.

Main Results:

  • Tumors deficient in DNAJA2 exhibit enhanced sensitivity to ICB therapy.
  • DNAJA2 depletion leads to elevated centriolar satellite proteins (PCM1, CEP290), causing aberrant mitosis and chromosome instability.
  • This mitotic dysfunction activates the cGAS-STING pathway, improving ICB therapy outcomes.

Conclusions:

  • DNAJA2 plays a critical role in regulating mitotic division and chromosome stability.
  • Targeting DNAJA2 or related pathways (CMA) could enhance cancer immunotherapy efficacy.
  • DNAJA2 is a promising target for advancing HSP-based cancer therapies and improving treatment strategies.

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