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. Epub 2024 Aug 22.

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.

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism
  • Autophagy
  • Cell Cycle Proteins* / genetics
  • Cell Cycle Proteins* / metabolism
  • Cellular Senescence*
  • Chromatin / genetics
  • Chromatin / metabolism
  • HEK293 Cells
  • Histone Chaperones* / genetics
  • Histone Chaperones* / metabolism
  • Histones / genetics
  • Histones / metabolism
  • Humans
  • Inflammation* / genetics
  • Inflammation* / metabolism
  • Inflammation* / pathology
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • NF-kappa B* / genetics
  • NF-kappa B* / metabolism
  • Nuclear Proteins* / genetics
  • Nuclear Proteins* / metabolism
  • Nucleotidyltransferases
  • Promyelocytic Leukemia Protein* / genetics
  • Promyelocytic Leukemia Protein* / metabolism
  • Protein Serine-Threonine Kinases* / genetics
  • Protein Serine-Threonine Kinases* / metabolism
  • Sequestosome-1 Protein* / genetics
  • Sequestosome-1 Protein* / metabolism
  • Signal Transduction*
  • Transcription Factors* / genetics
  • Transcription Factors* / metabolism
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • Cell Cycle Proteins
  • cGAS protein, human
  • Chromatin
  • HIRA protein, human
  • Histone Chaperones
  • Histones
  • Membrane Proteins
  • NF-kappa B
  • Nuclear Proteins
  • Nucleotidyltransferases
  • PML protein, human
  • Promyelocytic Leukemia Protein
  • Protein Serine-Threonine Kinases
  • Sequestosome-1 Protein
  • SQSTM1 protein, human
  • STING1 protein, human
  • TBK1 protein, human
  • Transcription Factors
  • Tumor Suppressor Proteins