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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 5487-5492 |
| Number of pages | 6 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Volume | 116 |
| Issue number | 12 |
| DOIs | |
| State | Published - 2019 |
Funding
We thank Drs. Sheng Zhang and Ievgen Motorykin for help with the SILAC experiments, Cornell University Imaging Facility for confocal microscopy, which is supported by NIH Grant S10RR025502, and Cornell University NMR Facility, which is supported by NSF Grant CHE-1531632. This work is supported by Howard Hughes Medical Institute, Cornell University, and a grant from NIH/National Institute of Diabetes and Digestive and Kidney Diseases, DK107868. The Orbitrap Fusion mass spectrometer is supported by NIH Grant SIG 1S10 OD017992-01. ACKNOWLEDGMENTS. We thank Drs. Sheng Zhang and Ievgen Motorykin for help with the SILAC experiments, Cornell University Imaging Facility for confocal microscopy, which is supported by NIH Grant S10RR025502, and Cornell University NMR Facility, which is supported by NSF Grant CHE-1531632. This work is supported by Howard Hughes Medical Institute, Cornell University, and a grant from NIH/National Institute of Diabetes and Digestive and Kidney Diseases, DK107868. The Orbitrap Fusion mass spectrometer is supported by NIH Grant SIG 1S10 OD017992-01.
Keywords
- HDAC11
- IFNAR1
- Interferon
- Lysine fatty acylation
- SHMT2
ASJC Scopus subject areas
- General