HDAC11 regulates type I interferon signaling through defatty-acylation of SHMT2
Open accessPublished version of a preprint
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.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
HDAC11 can remove long chain fatty-acyl groups from H3K9 peptides.
“It can remove long chain fatty-acyl groups from H3K9 peptides.”
From HDACs and the epigenetic plasticity of cancer cells: target the complexity (2022) · cites this paper as Cao et al., 2019
HDAC11 is 10,000 times more effective than other HDACs such as HDAC8 at defatty-acylase activity.
“As mentioned earlier, defatty-acylase activity has also been observed with other HDACs such as HDAC8, but HDAC11 is 10,000 times more effective (Cao et al., 2019).”
From HDACs and the epigenetic plasticity of cancer cells: target the complexity (2022) · cites this paper as Cao et al., 2019
HDAC11 shows strong defatty-acylase activity.
“Instead, HDAC11 shows strong defatty-acylase activity.”
From HDACs and the epigenetic plasticity of cancer cells: target the complexity (2022) · cites this paper as Cao et al., 2019
Through de-fatty acid acylation of SHMT2a, HDAC11 may downregulate the immune response associated with type I IFN.
“Through de-fatty acid acylation of SHMT2a, HDAC11 may downregulate the immune response associated with type I IFN.(Cao et al., 2019).”
From HDACs and the epigenetic plasticity of cancer cells: target the complexity (2022) · cites this paper as Cao et al., 2019
SHMT expression is associated with immune response transcriptional programs in ACC and LGG patient cohorts.
“Previous studies have identified links between SHMT proteins and interferon signaling, and these findings indicate SHMT expression is associated with immune response transcriptional programs in ACC and LGG patient cohorts.”
From A review of small-molecule inhibitors of one-carbon enzymes: SHMT2 and MTHFD2 in the spotlight (2021) · cites this paper as [131]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Haberland, M., Montgomery, R. L., & Olson, E. N. (2008) · Nature Reviews Genetics · doi:10.1038/nrg2485 · Cited by 2,541 · see citing works
Erasers of Histone Acetylation: The Histone Deacetylase EnzymesPreprint
Seto, E., & Yoshida, M. (2014) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a018713 · Cited by 2,019 · see citing works
Self-citationGregoretti, I., Lee, Y.-M., & Goodson, H. V. (2004) · Journal of Molecular Biology · doi:10.1016/j.jmb.2004.02.006 · Cited by 1,456 · see citing works
Sirt5 Is a NAD-Dependent Protein Lysine Demalonylase and Desuccinylase
Du, J., Zhou, Y., Su, X., Yu, J. J., Khan, S., Jiang, H., Kim, J., Woo, J., Kim, J. H., Choi, B. H., et al. (2011) · Science · doi:10.1126/science.1207861 · Cited by 1,429 · see citing works
Self-citationThe Rpd3/Hda1 family of lysine deacetylases: from bacteria and yeast to mice and men
Yang, X., & Seto, E. (2008) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2346 · Cited by 1,239 · see citing works
Self-citationThe first identification of lysine malonylation substrates and its regulatory enzyme
Peng, C., Lu, Z., Xie, Z., Cheng, Z., Chen, Y., Tan, M., Luo, H., Zhang, Y., He, W., Yang, K., et al. (2011) · Molecular & Cellular Proteomics · doi:10.1074/mcp.m111.012658 · Cited by 751 · see citing works
Gao, L., Cueto, M. A., Asselbergs, F., & Atadja, P. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m111871200 · Cited by 744 · see citing works
SIRT6 regulates TNF-α secretion through hydrolysis of long-chain fatty acyl lysine
Jiang, H., Khan, S., Wang, Y., Charron, G., He, B., Sebastian, C., Du, J., Kim, R., Ge, E., Mostoslavsky, R., et al. (2013) · Nature · doi:10.1038/nature12038 · Cited by 697 · see citing works
Self-citationFeldman, J. L., Baeza, J., & Denu, J. M. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.c113.511261 · Cited by 637 · cited 1× · see citing works
“The studies with HDAC11 suggest that the zinc-dependent HDACs are similar to the sirtuin family of HDACs, where several members preferentially recognize acyl lysine modifications other than acetyl lysine, while some can remove multiple modifications with similar efficiencies (11, 13).”
BackgroundThe histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance
Villagra, A., Cheng, F., Wang, H.-W., Suarez, I., Glozak, M., Maurin, M., Nguyen, D., Wright, K. L., Atadja, P. W., Bhalla, K., et al. (2009) · Nature Immunology · doi:10.1038/ni.1673 · Cited by 455 · see citing works
Self-citationType I Interferon Receptors: Biochemistry and Biological Functions
de Weerd, N. A., Samarajiwa, S., & Hertzog, P. J. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.r700006200 · Cited by 390 · see citing works
SHMT2 drives glioma cell survival in ischaemia but imposes a dependence on glycine clearance
Kim, D., Fiske, B. P., Birsoy, K., Freinkman, E., Kami, K., Possemato, R. L., Chudnovsky, Y., Pacold, M. E., Chen, W. W., Cantor, J. R., et al. (2015) · Nature · doi:10.1038/nature14363 · Cited by 368 · see citing works
The Mechanism of Action of Interferon-β in Relapsing Multiple Sclerosis
Kieseier, B. C. (2011) · CNS Drugs · doi:10.2165/11591110-000000000-00000 · Cited by 308 · see citing works
Robust Fluorescent Detection of Protein Fatty-Acylation with Chemical Reporters
Charron, G., Zhang, M. M., Yount, J. S., Wilson, J. P., Raghavan, A. S., Shamir, E. R., & Hang, H. C. (2009) · Journal of the American Chemical Society · doi:10.1021/ja810122f · Cited by 301 · see citing works
Sirtuins in Epigenetic Regulation
Jing, H., & Lin, H. (2015) · Chemical Reviews · doi:10.1021/cr500457h · Cited by 271 · see citing works
Self-citationRadioactive assay for serine transhydroxymethylase
Taylor, R. T., & Weissbach, H. (1965) · Analytical Biochemistry · doi:10.1016/0003-2697(65)90120-x · Cited by 204 · see citing works
SHMT1 and SHMT2 Are Functionally Redundant in Nuclear De novo Thymidylate Biosynthesis
Anderson, D. D., & Stover, P. J. (2009) · PLoS ONE · doi:10.1371/journal.pone.0005839 · Cited by 199 · see citing works
Identification of a de novo thymidylate biosynthesis pathway in mammalian mitochondria
Anderson, D. D., Quintero, C. M., & Stover, P. J. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1103623108 · Cited by 186 · see citing works
Immunomodulatory and antitumor effects of type I interferons and their application in cancer therapy
Medrano, R. F. V., Hunger, A., Mendonça, S. A., Barbuto, J. A. M., & Strauss, B. E. (2017) · Oncotarget · doi:10.18632/oncotarget.19531 · Cited by 185 · see citing works
Histone deacetylase 11 is a fatty-acid deacylase
Kutil, Z., Novakova, Z., Meleshin, M., Mikesova, J., Schutkowski, M., & Barinka, C. (2018) · ACS Chemical Biology · doi:10.1021/acschembio.7b00942 · Cited by 174 · see citing works
Histone deacetylase 11 is an ε-N-Myristoyllysine hydrolase
Moreno-Yruela, C., Galleano, I., Madsen, A. S., & Olsen, C. A. (2018) · Cell Chemical Biology · doi:10.1016/j.chembiol.2018.04.007 · Cited by 149 · see citing works
Stevenson, F. T., Bursten, S. L., Fanton, C. P., Locksley, R. M., & Lovett, D. H. (1993) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.90.15.7245 · Cited by 147 · see citing works
Madsen, A. S., & Olsen, C. A. (2012) · Angewandte Chemie International Edition · doi:10.1002/anie.201203754 · Cited by 122 · see citing works
Sahakian, E., Powers, J. J., Chen, J., Deng, S., Cheng, F., Graeter, A. I., Woods, D. M., Rock-Klotz, J. A., Sodré, A. L., Youn, J., et al. (2014) · Molecular Immunology · doi:10.1016/j.molimm.2014.08.002 · Cited by 120 · see citing works
HDAC11 plays an essential role in regulating OX40 ligand expression in Hodgkin lymphoma
Buglio, D., Khaskhely, N. M., Voo, K. S., Martínez-Valdez, H., Liu, Y., & Younes, A. (2011) · Blood · doi:10.1182/blood-2010-08-303701 · Cited by 119 · see citing works
HDAC8 catalyzes the hydrolysis of long chain fatty acyl lysine
Aramsangtienchai, P., Spiegelman, N. A., He, B., Miller, S. P., Dai, L., Zhao, Y., & Lin, H. (2016) · ACS Chemical Biology · doi:10.1021/acschembio.6b00396 · Cited by 118 · see citing works
Self-citationMyristyl acylation of the tumor necrosis factor alpha precursor on specific lysine residues.
Stevenson, F. T., Bursten, S. L., Locksley, R. M., & Lovett, D. H. (1992) · The Journal of experimental medicine · doi:10.1084/jem.176.4.1053 · Cited by 117 · see citing works
HDAC11 is a novel drug target in carcinomas
Deubzer, H. E., Schier, M. C., Oehme, I., Lodrini, M., Haendler, B., Sommer, A., & Witt, O. (2013) · International Journal of Cancer · doi:10.1002/ijc.27876 · Cited by 112 · see citing works
Giardina, G., Brunotti, P., Fiascarelli, A., Cicalini, A., Costa, M. G. S., Buckle, A. M., di Salvo, M. L., Giorgi, A., Marani, M., Paone, A., et al. (2015) · FEBS Journal · doi:10.1111/febs.13211 · Cited by 104 · see citing works
A BRISC-SHMT Complex Deubiquitinates IFNAR1 and Regulates Interferon Responses
Zheng, H., Gupta, V., Patterson-Fortin, J., Bhattacharya, S., Katlinski, K., Wu, J., Varghese, B., Carbone, C. J., Aressy, B., Fuchs, S. Y., et al. (2013) · Cell Reports · doi:10.1016/j.celrep.2013.08.025 · Cited by 101 · see citing works
SIRT2 and lysine fatty acylation regulate the transforming activity of K-Ras4a
Jing, H., Zhang, X., Wisner, S., Chen, X., Spiegelman, N. A., Linder, M. E., & Lin, H. (2017) · eLife · doi:10.7554/elife.32436 · Cited by 99 · see citing works
Self-citationIdentifying the functional contribution of the defatty-acylase activity of SIRT6
Zhang, X., Khan, S., Jiang, H. X., Antonyak, M. A., Chen, X., Spiegelman, N. A., Shrimp, J. H., Cerione, R. A., & Lin, H. (2016) · Nature Chemical Biology · doi:10.1038/nchembio.2106 · Cited by 88 · see citing works
Self-citationSIRT6 regulates Ras-related protein R-Ras2 by lysine defatty-acylation
Zhang, X., Spiegelman, N. A., Nelson, O. D., Jing, H., & Lin, H. (2017) · eLife · doi:10.7554/elife.25158 · Cited by 86 · see citing works
Self-citationThiomyristoyl peptides as cell-permeable Sirt6 inhibitors
He, B., Hu, J., Zhang, X., & Lin, H. (2014) · Organic & Biomolecular Chemistry · doi:10.1039/c4ob00860j · Cited by 73 · see citing works
Self-citationPlasmodium falciparum Sir2A Preferentially Hydrolyzes Medium and Long Chain Fatty Acyl Lysine
Zhu, A. Y., Zhou, Y., Khan, S., Deitsch, K., Hao, Q., & Lin, H. (2011) · ACS Chemical Biology · doi:10.1021/cb200230x · Cited by 67 · see citing works
Self-citationTriggering ubiquitination of IFNAR1 protects tissues from inflammatory injury
Bhattacharya, S., Katlinski, K. V., Reichert, M., Takano, S., Brice, A. K., Zhao, B., Yu, Q., Zheng, H., Carbone, C. J., Katlinskaya, Y. V., et al. (2014) · EMBO Molecular Medicine · doi:10.1002/emmm.201303236 · Cited by 63 · see citing works
Antiviral therapy of hepatitis delta virus infection — progress and challenges towards cure
Wranke, A., & Wedemeyer, H. H. (2016) · Current Opinion in Virology · doi:10.1016/j.coviro.2016.10.002 · Cited by 33 · see citing works
Li, M., Zhu, M., Linghu, E., Feng, F., Zhu, B., Wu, C., & Guo, M. (2016) · Oncotarget · doi:10.18632/oncotarget.13107 · Cited by 17 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Histone deacetylase 11 is an ε-N-Myristoyllysine hydrolase
Moreno-Yruela, C., Galleano, I., Madsen, A. S., & Olsen, C. A. (2018) · Cell Chemical Biology · doi:10.1016/j.chembiol.2018.04.007 · Cited by 149 · see citing works
Strategies To Design Selective Histone Deacetylase Inhibitors
Melesina, J., Simoben, C. V., Praetorius, L., Bülbül, E. F., Robaa, D., & Sippl, W. (2021) · ChemMedChem · doi:10.1002/cmdc.202000934 · Cited by 118 · see citing works
HDAC11 suppresses the thermogenic program of adipose tissue via BRD2
Bagchi, R. A., Ferguson, B. S., Stratton, M. S., Hu, T., Cavasin, M. A., Sun, L., Lin, Y.-H., Liu, D., Londono, P., Song, K., et al. (2018) · JCI Insight · doi:10.1172/jci.insight.120159 · Cited by 110 · see citing works
Regulatory mechanisms of one-carbon metabolism enzymes
Petrova, B., Maynard, A. G., Wang, P., & Kanarek, N. (2023) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2023.105457 · Cited by 103 · see citing works
Metabolic control of BRISC-SHMT2 assembly regulates immune signalling
Walden, M., Tian, L., Ross, R. L., Sykora, U. M., Byrne, D. P., Hesketh, E. L., Masandi, S. K., Cassel, J., George, R., Ault, J. R., et al. (2019) · Nature · doi:10.1038/s41586-019-1232-1 · Cited by 85 · see citing works
A review of small-molecule inhibitors of one-carbon enzymes: SHMT2 and MTHFD2 in the spotlight
Cuthbertson, C. R., Arabzada, Z., Bankhead, A., Kyani, A., & Neamati, N. (2021) · ACS Pharmacology & Translational Science · doi:10.1021/acsptsci.0c00223 · Cited by 57 · see citing works
HDACs and the epigenetic plasticity of cancer cells: target the complexity
Brancolini, C., Gagliano, T., & Minisini, M. (2022) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2022.108190 · Cited by 55 · see citing works
Mostofa, A., Distler, A., Meads, M. B., Sahakian, E., Powers, J. J., Achille, A., Noyes, D., Wright, G., Fang, B., Izumi, V., et al. (2021) · JCI Insight · doi:10.1172/jci.insight.151713 · Cited by 27 · see citing works
Baselious, F., Robaa, D., & Sippl, W. (2023) · Computers in Biology and Medicine · doi:10.1016/j.compbiomed.2023.107700 · Cited by 20 · see citing works
- Authors
- Cao, J., Sun, L., Aramsangtienchai, P., Spiegelman, N. A., Zhang, X., Huang, W., Seto, E., & Lin, H.
- Affiliations
- Cornell University (US)
- George Washington University (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Lin, Hening
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2019-02-28
- Volume
- 116
- Issue
- 12
- Pages
- 5487-5492
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC6431144
- OpenAlex
- W2766922695
- Cited by
- 189
- References
- 38
- Citations by year
- 2026: 22 · 2025: 25 · 2024: 26 · 2023: 23 · 2022: 20 · 2021: 30 · 2020: 23 · 2019: 16 · 2018: 2 · 2013: 1
- FWCI
- 7.37
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion, cc-by-nc-nd)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Civil War Book Review (submittedVersion)
- Funders
- HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (DK107868)
- HHS | National Institutes of Health (S10RR025502, 1S10 OD017992-01)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- HDAC11, SHMT2, type I interferon signaling, protein surface exposure, histone deacetylase, immune regulation
- MeSH terms
- Acylation, Animals, Histone Deacetylases, Humans, Interferon Type I, Glycine Hydroxymethyltransferase, Signal Transduction, Mice, Knockout, Hydroxymethyl and Formyl Transferases, Mice, HEK293 Cells
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
