HDAC11 regulates type I interferon signaling through defatty-acylation of SHMT2
| Autor: | Pornpun Aramsangtienchai, Xiaoyu Zhang, Nicole A Spiegelman, Ji Cao, Hening Lin, Weishan Huang, Lei Sun, Edward Seto |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Hydroxymethyl and Formyl Transferases Acylation Biology Biochemistry Histone Deacetylases 03 medical and health sciences Mice Ubiquitin Interferon HDAC11 medicine Animals Humans IFNAR1 Glycine Hydroxymethyltransferase Mice Knockout Histone deacetylase 5 Multidisciplinary 030102 biochemistry & molecular biology Histone deacetylase 2 interferon Biological Sciences SHMT2 030104 developmental biology HEK293 Cells Interferon Type I biology.protein lysine fatty acylation Histone deacetylase Fatty acylation medicine.drug Deacetylase activity Signal Transduction |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America |
| ISSN: | 1091-6490 0027-8424 |
| Popis: | Significance HDAC11 is the only class IV member of the histone deacetylase (HDAC) family, and very little is known about its biological function. The work here reveals its efficient and physiologically relevant activity. The regulation of SHMT2 and interferon signaling expands the known biological function of protein lysine fatty acylation, which has only recently started to be appreciated. Furthermore, a compelling molecular mechanism is proposed to connect HDAC11 to immune response. The finding opens exciting opportunities to develop HDAC11-specific inhibitors to treat human diseases that would benefit from increased type I interferon signaling, such as viral infection, multiple sclerosis, and cancer. 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. |
| Databáze: | OpenAIRE |
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