2. Academic Validation
  3. HDAC11 regulates type I interferon signaling through defatty-acylation of SHMT2

HDAC11 regulates type I interferon signaling through defatty-acylation of SHMT2

  • Proc Natl Acad Sci U S A. 2019 Mar 19;116(12):5487-5492. doi: 10.1073/pnas.1815365116.
Ji Cao 1 2,  Lei Sun 3,  Pornpun Aramsangtienchai 1,  Nicole A Spiegelman 1,  Xiaoyu Zhang 1,  Weishan Huang 4,  Edward Seto 3,  Hening Lin 5 6
Affiliations

Affiliations

  • 1 Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853.
  • 2 Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, 310058 Hangzhou, China.
  • 3 George Washington University Cancer Center, Washington, DC 20037.
  • 4 Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853.
  • 5 Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853; [email protected].
  • 6 Howard Hughes Medical Institute, Cornell University, Ithaca, NY 14853.
PMID: 30819897 DOI: 10.1073/pnas.1815365116
Abstract

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.

Keywords

HDAC11; IFNAR1; SHMT2; interferon; lysine fatty acylation.

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