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Histone chaperone HIRA, promyelocytic leukemia protein, and p62/SQSTM1 coordinate to regulate inflammation during cell senescence.
- Source :
-
Molecular cell [Mol Cell] 2024 Sep 05; Vol. 84 (17), pp. 3271-3287.e8. Date of Electronic Publication: 2024 Aug 22. - Publication Year :
- 2024
-
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.<br />Competing Interests: Declaration of interests The authors declare no competing interests.<br /> (Copyright © 2024 Elsevier Inc. All rights reserved.)
- Subjects :
- Humans
Tumor Suppressor Proteins metabolism
Tumor Suppressor Proteins genetics
Adaptor Proteins, Signal Transducing metabolism
Adaptor Proteins, Signal Transducing genetics
Membrane Proteins metabolism
Membrane Proteins genetics
Animals
Mice
HEK293 Cells
Histones metabolism
Histones genetics
Chromatin metabolism
Chromatin genetics
Autophagy
Nucleotidyltransferases
Promyelocytic Leukemia Protein metabolism
Promyelocytic Leukemia Protein genetics
Cellular Senescence
Sequestosome-1 Protein metabolism
Sequestosome-1 Protein genetics
Histone Chaperones metabolism
Histone Chaperones genetics
Cell Cycle Proteins metabolism
Cell Cycle Proteins genetics
NF-kappa B metabolism
NF-kappa B genetics
Protein Serine-Threonine Kinases metabolism
Protein Serine-Threonine Kinases genetics
Nuclear Proteins metabolism
Nuclear Proteins genetics
Inflammation metabolism
Inflammation pathology
Inflammation genetics
Transcription Factors metabolism
Transcription Factors genetics
Signal Transduction
Subjects
Details
- Language :
- English
- ISSN :
- 1097-4164
- Volume :
- 84
- Issue :
- 17
- Database :
- MEDLINE
- Journal :
- Molecular cell
- Publication Type :
- Academic Journal
- Accession number :
- 39178863
- Full Text :
- https://doi.org/10.1016/j.molcel.2024.08.006