细胞衰老是一种与炎症衰老相关分泌表型 (SASP) 相关的应激诱导的稳定增殖停滞，是衰老的一个原因。在衰老细胞中，细胞质染色质片段 (CCF) 通过抗病毒 cGAS/STING 途径激活 SASP。早幼粒细胞白血病 (PML) 蛋白组织 PML 核体 (NB)，其也参与衰老和抗病毒免疫。 HIRA 组蛋白 H3.3 伴侣定位于衰老细胞中的 PML NB。在这里，我们表明 HIRA 和 PML 对于 SASP 表达至关重要，与 HIRA 对 PML NB 的定位紧密相关。 HIRA 失活不会直接阻断核因子 κB (NF-κB) 靶基因的表达。相反，H3.3 独立的 HIRA 功能通过 CCF-cGAS-STING-TBK1-NF-κB 途径激活 SASP。 HIRA 与 p62/SQSTM1（一种自噬调节因子和负 SASP 调节因子）发生物理相互作用。 HIRA 和 p62 共定位于 PML NB，与其对 SASP 的拮抗调节有关，PML NB 控制其空间配置。这些结果概述了 HIRA 和 PML 在 SASP 监管中的作用。版权所有 © 2024 Elsevier Inc. 保留所有权利。

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.Copyright © 2024 Elsevier Inc. All rights reserved.