O-GlcNAc modification of small heat shock proteins enhances their anti-amyloid chaperone activity

Nat Chem. 2021 May;13(5):441-450. doi: 10.1038/s41557-021-00648-8. Epub 2021 Mar 15.


A major role for the intracellular post-translational modification O-GlcNAc appears to be the inhibition of protein aggregation. Most of the previous studies in this area focused on O-GlcNAc modification of the amyloid-forming proteins themselves. Here we used synthetic protein chemistry to discover that O-GlcNAc also activates the anti-amyloid activity of certain small heat shock proteins (sHSPs), a potentially more important modification event that can act broadly and substoichiometrically. More specifically, we found that O-GlcNAc increases the ability of sHSPs to block the amyloid formation of both α-synuclein and Aβ(1-42). Mechanistically, we show that O-GlcNAc near the sHSP IXI-domain prevents its ability to intramolecularly compete with substrate binding. Finally, we found that, although O-GlcNAc levels are globally reduced in Alzheimer's disease brains, the modification of relevant sHSPs is either maintained or increased, which suggests a mechanism to maintain these potentially protective O-GlcNAc modifications. Our results have important implications for neurodegenerative diseases associated with amyloid formation and potentially other areas of sHSP biology.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid / antagonists & inhibitors*
  • Heat-Shock Proteins, Small / metabolism*
  • Humans
  • N-Acetylglucosaminyltransferases / metabolism*


  • Amyloid
  • Heat-Shock Proteins, Small
  • N-Acetylglucosaminyltransferases
  • O-GlcNAc transferase