HDAC11 regulates type I interferon signaling through defatty-acylation of SHMT2 Academic Article uri icon


MeSH Major

  • Archaeal Proteins
  • Histidine
  • Methyltransferases
  • Peptide Elongation Factor 2
  • Pyrococcus horikoshii


  • The smallest histone deacetylase (HDAC) and the only class IV HDAC member, HDAC11, is reported to regulate immune activation and tumorigenesis, yet its biochemical function is largely unknown. Here we identify HDAC11 as an efficient lysine defatty-acylase that is >10,000-fold more efficient than its deacetylase activity. Through proteomics studies, we hypothesized and later biochemically validated SHMT2 as a defatty-acylation substrate of HDAC11. HDAC11-catalyzed defatty-acylation did not affect the enzymatic activity of SHMT2. Instead, it affects the ability of SHMT2 to regulate type I IFN receptor ubiquitination and cell surface level. Correspondingly, HDAC11 depletion increased type I IFN signaling in both cell culture and mice. This study not only demonstrates that HDAC11 has an activity that is much more efficient than the corresponding deacetylase activity, but also expands the physiological functions of HDAC11 and protein lysine fatty acylation, which opens up opportunities to develop HDAC11-specific inhibitors as therapeutics to modulate immune responses.

publication date

  • January 2019



  • Academic Article



  • eng

PubMed Central ID

  • PMC6431144

Digital Object Identifier (DOI)

  • 10.1073/pnas.1815365116

PubMed ID

  • 30819897

Additional Document Info

start page

  • 5487

end page

  • 5492


  • 116


  • 12