p16-dependent increase of PD-L1 stability regulates immunosurveillance of senescent cells

IF 17.3 1区 生物学 Q1 CELL BIOLOGY
Julia Majewska, Amit Agrawal, Avi Mayo, Lior Roitman, Rishita Chatterjee, Jarmila Sekeresova Kralova, Tomer Landsberger, Yonatan Katzenelenbogen, Tomer Meir-Salame, Efrat Hagai, Ilanit Sopher, Juan-Felipe Perez-Correa, Wolfgang Wagner, Avi Maimon, Ido Amit, Uri Alon, Valery Krizhanovsky
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Abstract

The accumulation of senescent cells promotes ageing and age-related diseases, but molecular mechanisms that senescent cells use to evade immune clearance and accumulate in tissues remain to be elucidated. Here we report that p16-positive senescent cells upregulate the immune checkpoint protein programmed death-ligand 1 (PD-L1) to accumulate in ageing and chronic inflammation. We show that p16-mediated inhibition of cell cycle kinases CDK4/6 induces PD-L1 stability in senescent cells via downregulation of its ubiquitin-dependent degradation. p16-expressing senescent alveolar macrophages elevate PD-L1 to promote an immunosuppressive environment that can contribute to an increased burden of senescent cells. Treatment with activating anti-PD-L1 antibodies engaging Fcγ receptors on effector cells leads to the elimination of PD-L1 and p16-positive cells. Our study uncovers a molecular mechanism of p16-dependent regulation of PD-L1 protein stability in senescent cells and reveals the potential of targeting PD-L1 to improve immunosurveillance of senescent cells and ameliorate senescence-associated inflammation. Majewska et al. show that p16-expressing senescent cells enhance the stability of the immune checkpoint PD-L1 by downregulating its proteasome-mediated ubiquitin-dependent degradation, leading to their accumulation in ageing and chronic inflammation.

Abstract Image

Abstract Image

p16 依赖性 PD-L1 稳定性的增加可调节衰老细胞的免疫监视。
衰老细胞的积累会促进衰老和与年龄有关的疾病,但衰老细胞逃避免疫清除并在组织中积累的分子机制仍有待阐明。在这里,我们报告了 p16 阳性衰老细胞上调免疫检查点蛋白程序性死亡配体 1(PD-L1),从而在衰老和慢性炎症中积聚。我们发现,p16 介导的细胞周期激酶 CDK4/6 抑制通过下调泛素依赖性降解诱导 PD-L1 在衰老细胞中的稳定性。激活效应细胞上 Fcγ 受体的抗 PD-L1 抗体可清除 PD-L1 和 p16 阳性细胞。我们的研究揭示了衰老细胞中 p16 依赖性调控 PD-L1 蛋白稳定性的分子机制,并揭示了靶向 PD-L1 改善衰老细胞免疫监视和改善衰老相关炎症的潜力。
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来源期刊
Nature Cell Biology
Nature Cell Biology 生物-细胞生物学
CiteScore
28.40
自引率
0.90%
发文量
219
审稿时长
3 months
期刊介绍: Nature Cell Biology, a prestigious journal, upholds a commitment to publishing papers of the highest quality across all areas of cell biology, with a particular focus on elucidating mechanisms underlying fundamental cell biological processes. The journal's broad scope encompasses various areas of interest, including but not limited to: -Autophagy -Cancer biology -Cell adhesion and migration -Cell cycle and growth -Cell death -Chromatin and epigenetics -Cytoskeletal dynamics -Developmental biology -DNA replication and repair -Mechanisms of human disease -Mechanobiology -Membrane traffic and dynamics -Metabolism -Nuclear organization and dynamics -Organelle biology -Proteolysis and quality control -RNA biology -Signal transduction -Stem cell biology
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