Institut Pasteur, Unité des Interactions Bactéries-Cellules, Paris, France; Institut National de la Santé et de la Recherche Médicale, U604, Paris, France; Institut National de la Recherche Agronomique, USC2020, Paris, France; Institut Pasteur, Chromatine et Infection G5, Paris, France.
Institut Pasteur, Chromatine et Infection G5, Paris, France.
Cell Rep. 2018 Apr 24;23(4):1124-1137. doi: 10.1016/j.celrep.2018.03.116.
Sirtuin 2 is a nicotinamide-adenine-dinucleotide-dependent deacetylase that regulates cell processes such as carcinogenesis, cell cycle, DNA damage, and infection. Subcellular localization of SIRT2 is crucial for its function but is poorly understood. Infection with the bacterial pathogen Listeria monocytogenes, which relocalizes SIRT2 from the cytoplasm to the chromatin, provides an ideal stimulus for the molecular study of this process. In this report, we provide a map of SIRT2 post-translational modification sites and focus on serine 25 phosphorylation. We show that infection specifically induces dephosphorylation of S25, an event essential for SIRT2 chromatin association. Furthermore, we identify a nuclear complex formed by the phosphatases PPM1A and PPM1B, with SIRT2 essential for controlling H3K18 deacetylation and SIRT2-mediated gene repression during infection and necessary for a productive Listeria infection. This study reveals a molecular mechanism regulating SIRT2 function and localization, paving the way for understanding other SIRT2-regulated cellular processes.
Sirtuin 2 是一种烟酰胺腺嘌呤二核苷酸依赖性去乙酰化酶，它调节细胞过程，如致癌作用、细胞周期、DNA 损伤和感染。SIRT2 的亚细胞定位对其功能至关重要，但了解甚少。细菌病原体李斯特菌感染会将 SIRT2 从细胞质重新定位到染色质，为研究这一过程的分子机制提供了理想的刺激。在本报告中，我们提供了 SIRT2 翻译后修饰位点图谱，并重点关注丝氨酸 25 磷酸化。我们发现感染特异性诱导 S25 的去磷酸化，这是 SIRT2 与染色质结合所必需的事件。此外，我们鉴定了一个由磷酸酶 PPM1A 和 PPM1B 组成的核复合物，其中 SIRT2 对于控制 H3K18 去乙酰化和 SIRT2 介导的感染期间的基因抑制是必不可少的，并且对于李斯特菌的有效感染也是必要的。这项研究揭示了调节 SIRT2 功能和定位的分子机制，为理解其他 SIRT2 调节的细胞过程铺平了道路。
