SIRT1 is downregulated by autophagy in senescence and ageing
Authors: Melanie Ott
Vemika Chandra
Peter D Adams
Shelley L Berger
Ravi Amaravadi
Jing Jiang
Jeffrey D Winkler
Zhixun Dou
Congcong Lu
Lu Wang
Terje Johansen
Wei Tong
Corey Bretz
Benjamin A Garcia
Caiyue Xu
Gry Evjen
Michael Nicastri
Parinaz Fozouni
Journal: Nature Cell Biology (2020)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: SIRT1; autophagy; protein homeostasis; ageing; metabolism
Affiliations: Penn Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Gladstone Institute of Virology, Gladstone Institutes, San Francisco, CA, USA., Department of Medicine, University of California, San Francisco, San Francisco, CA, USA., Molecular Cancer Research Group, Department of Medical Biology, University of Tromsø-The Arctic University of Norway, Tromsø, Norway., Division of Hematology, Children's Hospital of Philadelphia, Philadelphia, PA, USA., Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA., Institute of Translational Medicine, School of Medicine, Yangzhou University, Yangzhou, China., Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Department of Chemistry, University of Pennsylvania, Philadelphia, PA, USA., Sanford Burnham Prebys Medical Discovery Institute, San Diego, CA, USA., Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Penn Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. ., Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. ., Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, USA. ., Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA. ., Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA. ., Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. ., Department of Biology, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA, USA. .

Abstract:  SIRT1 (Sir2) is an NAD+-dependent deacetylase that plays critical roles in a broad range of biological events, including metabolism, the immune response and ageing1-5. 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. 

Retracted: No

PubPeer comments:
 In Figure 1d and e (Pro), the plottet data points are identical to each other, but the relative FPKM values are different. In Figure 2f and h, the plottet data points for Eto Day 9 (f) and Sirt (h) are almost identical to each other, but the values for % cells with cytoplasmic Sirt are different. In the source data for the Western immunoblots presented in Figure 1a,b and c, the individual membranes for Cyclin A and Lamin B1 show overlapping areas, indicating that they are not from the same gel. In Figure 1b, this is clearly seen with the Lamin B1 bands appearing in the Cyclin A blot. Usually, membranes are cut so that the individual proteins are detected from the same gel, preferably without stripping and reprobing. In this study, this could have been done. Apparently they did not. Furthermore, MW markers should always been shown on every membrane. I see no reason to hide them. ![file] ![file] ,