RRC ID 53834
Author Kumar A, Daitsh Y, Ben-Aderet L, Qiq O, Elayyan J, Batshon G, Reich E, Maatuf YH, Engel S, Dvir-Ginzberg M.
Title A predicted unstructured C-terminal loop domain in SIRT1 is required for cathepsin B cleavage.
Journal J Cell Sci
Abstract The C-terminus of SIRT1 can be cleaved by cathepsin B at amino acid H533 to generate a lower-functioning, N-terminally intact 75 kDa polypeptide (75SIRT1) that might be involved in age-related pathologies. However, the mechanisms underlying cathepsin B docking to and cleavage of SIRT1 are unclear. Here, we first identified several 75SIRT1 variants that are augmented with aging correlatively with increased cathepsin B levels in various mouse tissues, highlighting the possible role of this cleavage event in age-related pathologies. Then, based on H533 point mutation and structural modeling, we generated a functionally intact ΔSIRT1 mutant, lacking the internal amino acids 528-543 (a predicted C-terminus loop domain), which exhibits resistance to cathepsin B cleavage in vitro and in cell cultures. Finally, we showed that cells expressing ΔSIRT1 under pro-inflammatory stress are more likely to undergo caspase 9- dependent apoptosis than those expressing 75SIRT1. Thus, our data suggest that the 15-amino acid predicted loop motif embedded in the C-terminus of SIRT1 is susceptible to proteolytic cleavage by cathepsin B, leading to the formation of several N-terminally intact SIRT1 truncated variants in various aging mouse tissues.This article has an associated First Person interview with the first author of the paper.
Volume 131(16)
Published 2018-8-20
DOI 10.1242/jcs.214973
PII jcs.214973
PMID 30054388
MeSH Animals Cathepsin B / metabolism* Cellular Senescence / physiology Computational Biology Female HEK293 Cells HeLa Cells Humans Male Mice Mice, 129 Strain Mice, Transgenic Protein Interaction Domains and Motifs* / genetics Protein Isoforms / chemistry Protein Isoforms / genetics Protein Isoforms / metabolism Protein Structure, Secondary Proteolysis* Sirtuin 1 / chemistry* Sirtuin 1 / genetics Sirtuin 1 / metabolism*
IF 4.573
Times Cited 2
Mice RBRC05323