2. Academic Validation
  3. Histone chaperone HIRA, promyelocytic leukemia protein, and p62/SQSTM1 coordinate to regulate inflammation during cell senescence

Histone chaperone HIRA, promyelocytic leukemia protein, and p62/SQSTM1 coordinate to regulate inflammation during cell senescence

  • Mol Cell. 2024 Sep 5;84(17):3271-3287.e8. doi: 10.1016/j.molcel.2024.08.006.
Nirmalya Dasgupta 1,  Xue Lei 1,  Christina Huan Shi 1,  Rouven Arnold 1,  Marcos G Teneche 1,  Karl N Miller 1,  Adarsh Rajesh 1,  Andrew Davis 1,  Valesca Anschau 2,  Alexandre R Campos 2,  Rebecca Gilson 3,  Aaron Havas 1,  Shanshan Yin 1,  Zong Ming Chua 1,  Tianhui Liu 1,  Jessica Proulx 1,  Michael Alcaraz 1,  Mohammed Iqbal Rather 4,  Josue Baeza 5,  David C Schultz 6,  Kevin Y Yip 1,  Shelley L Berger 7,  Peter D Adams 8
Affiliations

Affiliations

  • 1 Sanford Burnham Prebys Medical Discovery Institute, 10901 N Torrey Pines Road, La Jolla, CA 92037, USA.
  • 2 Proteomics Facility, Sanford Burnham Prebys Medical Discovery Institute, 10901 N Torrey Pines Road, La Jolla, CA 92037, USA.
  • 3 Biophotonics Core, Salk Institute for Biological Studies, 10010 N Torrey Pines Road, La Jolla, CA 92037, USA.
  • 4 Beatson Institute for Cancer Research and University of Glasgow, Garscube Estate, Glasgow G61 1BD, UK.
  • 5 Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 6 High Throughput Screening Core, Department of Microbiology, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 7 Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 8 Sanford Burnham Prebys Medical Discovery Institute, 10901 N Torrey Pines Road, La Jolla, CA 92037, USA. Electronic address: padams@sbpdiscovery.org.
PMID: 39178863 DOI: 10.1016/j.molcel.2024.08.006
Abstract

Cellular senescence, a stress-induced stable proliferation arrest associated with an inflammatory senescence-associated secretory phenotype (SASP), is a cause of aging. In senescent cells, cytoplasmic chromatin fragments (CCFs) activate SASP via the anti-viral cGAS/STING pathway. Promyelocytic leukemia (PML) protein organizes PML nuclear bodies (NBs), which are also involved in senescence and anti-viral immunity. The HIRA histone H3.3 chaperone localizes to PML NBs in senescent cells. Here, we show that HIRA and PML are essential for SASP expression, tightly linked to HIRA's localization to PML NBs. Inactivation of HIRA does not directly block expression of nuclear factor κB (NF-κB) target genes. Instead, an H3.3-independent HIRA function activates SASP through a CCF-cGAS-STING-TBK1-NF-κB pathway. HIRA physically interacts with p62/SQSTM1, an Autophagy regulator and negative SASP regulator. HIRA and p62 co-localize in PML NBs, linked to their antagonistic regulation of SASP, with PML NBs controlling their spatial configuration. These results outline a role for HIRA and PML in the regulation of SASP.

Keywords

CCF; HIRA; NF-κB pathway; PML; PML NBs; SASP; cGAS-STING signaling; p62/SQSTM; senescence.

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