Open AccessSIRT1 is downregulated by autophagy in senescence and ageing
Author(s) -
Caiyue Xu,
Lu Wang,
Parinaz Fozouni,
Gry Evjen,
Vemika Chandra,
Jing Jiang,
Congcong Lu,
Michael C. Nicastri,
Corey Bretz,
Jeffrey D. Winkler,
Ravi K. Amaravadi,
Benjamin A. García,
Peter D. Adams,
Mélanie Ott,
Wei Tong,
Terje Johansen,
Zhixun Dou,
Shelley L. Berger
Publication year - 2020
Publication title -
nature cell biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 11.38
H-Index - 369
eISSN - 1476-4679
pISSN - 1465-7392
DOI - 10.1038/s41556-020-00579-5
Subject(s) - autophagy , microbiology and biotechnology , senescence , biology , lysosome , haematopoiesis , downregulation and upregulation , mtorc1 , progenitor cell , stem cell , pi3k/akt/mtor pathway , signal transduction , biochemistry , apoptosis , enzyme , gene
SIRT1 (Sir2) is an NAD + -dependent deacetylase that plays critical roles in a broad range of biological events, including metabolism, the immune response and ageing 1-5 . Although there is strong interest in stimulating SIRT1 catalytic activity, the homeostasis of SIRT1 at the protein level is poorly understood. Here we report that macroautophagy (hereafter referred to as autophagy), a catabolic membrane trafficking pathway that degrades cellular components through autophagosomes and lysosomes, mediates the downregulation of mammalian SIRT1 protein during senescence and in vivo ageing. In senescence, nuclear SIRT1 is recognized as an autophagy substrate and is subjected to cytoplasmic autophagosome-lysosome degradation, via the autophagy protein LC3. Importantly, the autophagy-lysosome pathway contributes to the loss of SIRT1 during ageing of several tissues related to the immune and haematopoietic system in mice, including the spleen, thymus, and haematopoietic stem and progenitor cells, as well as in CD8 + CD28 - T cells from aged human donors. Our study reveals a mechanism in the regulation of the protein homeostasis of SIRT1 and suggests a potential strategy to stabilize SIRT1 to promote productive ageing.