Peer-reviewedCC BY 4.0JCI Insight
The E3 ubiquitin ligase HECTD3 controls immune colonic inflammation by restricting MyD88 activation and signaling
12 affiliations
- 1Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA.
- 2Department of Anatomy and Cell Biology, College of Medicine, University of Florida, Gainesville, Florida, USA.
- 3Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA.
- 4J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, Florida, USA.
- 5Department of Pharmacology and Toxicology, R. Ken Coit College of Pharmacy, Department of Chemistry and Biochemistry, College of Science & College of Medicine, The BIO5 Institute, The University of Arizona, Tucson, Arizona, USA.
- 6Taplin Mass Spectrometry Facility, Harvard Medical School, Boston, Massachusetts, USA.
- 7Department of Pharmacology and Therapeutics and
- 8Department of Microbiology and Cell Science, IFAS, University of Florida, Gainesville, Florida, USA.
- 9Department of Pathology, NYU School of Medicine, New York, New York, USA.
- 10Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Florida, Gainesville, Florida, USA.
- 11Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA.
- 12Department of Biochemistry & Molecular Biology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
Abstract
Ubiquitination is an important posttranslational modification associated with essential cellular processes. Here we show that deletion of E3 ubiquitin ligase HECTD3 — germline or in hematopoietic compartment, including in Cd11c+ cells — causes severe disease and increased production of proinflammatory cytokines in a murine model of ulcerative colitis (UC). HECTD3 mRNA levels were found reduced in colonic tissues of patients with UC, which highlights a potential role for HECTD3 in regulating inflammatory responses in UC. We identified MyD88, a central adaptor in the TLR/IL-1R signaling and inflammatory response, as a target for HECTD3 ubiquitination. We demonstrate that HECTD3 ubiquitinates MyD88 through K27-linked Poly-Ub chains in a nondegradative manner. HECTD3-KO GM-CSF–bone marrow–derived cells treated with the TLR4 ligand LPS produced more proinflammatory cytokines, showed elevated phosphorylation of NF-κB and IRAK4, as well as increased association of MyD88 with IRAK4, demonstrating that HECTD3 controls MyD88/IRAK4/NF-κB axis. Inhibition of MyD88 activity rescued colitis severity in the HECTD3-KO mice, including the elevated proinflammatory cytokine production. Thus, our results establish MyD88 as a target for HECTD3 nondegradative polyubiquitination and restriction of innate immune colonic inflammation.
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BibTeX
@article{islam2026ubiquitin,
title = {{The E3 ubiquitin ligase HECTD3 controls immune colonic inflammation by restricting MyD88 activation and signaling}},
author = {Shamima Islam and Shahnewaj Mannan and Ashley Zuniga and Upasana Parthasarathy and Valeriu B. Cismasiu and Leonardo Silvane and Sayan Chakraborty and Divya Priyanka Talada and Raghwendra Pratap Singh and Tomas Zelenka and Amreen Naveen and Sephra Chyanne Vickers and Michael G.M. Grant and Jonathan J. Cho and Theodore Drashansky and Alexander J. Kwiatkowski and Xintong Liu and Ross Tomaino and Olga A. Guryanova and Mariola J. Ferraro and Sang Yong Kim and Christian Jobin and Benjamin G. Keselowsky and Hongmin Li and Paulo C. Rodriguez and Martina Molgora and Amer A. Beg and Timothy I. Shaw and Zheng Ruan and Lixin Wan and Dorina Avram},
journal = {JCI Insight},
year = {2026},
month = sep,
doi = {10.1172/jci.insight.185437},
url = {https://doi.org/10.1172/jci.insight.185437},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - The E3 ubiquitin ligase HECTD3 controls immune colonic inflammation by restricting MyD88 activation and signaling
AU - Shamima Islam
AU - Shahnewaj Mannan
AU - Ashley Zuniga
AU - Upasana Parthasarathy
AU - Valeriu B. Cismasiu
AU - Leonardo Silvane
AU - Sayan Chakraborty
AU - Divya Priyanka Talada
AU - Raghwendra Pratap Singh
AU - Tomas Zelenka
AU - Amreen Naveen
AU - Sephra Chyanne Vickers
AU - Michael G.M. Grant
AU - Jonathan J. Cho
AU - Theodore Drashansky
AU - Alexander J. Kwiatkowski
AU - Xintong Liu
AU - Ross Tomaino
AU - Olga A. Guryanova
AU - Mariola J. Ferraro
AU - Sang Yong Kim
AU - Christian Jobin
AU - Benjamin G. Keselowsky
AU - Hongmin Li
AU - Paulo C. Rodriguez
AU - Martina Molgora
AU - Amer A. Beg
AU - Timothy I. Shaw
AU - Zheng Ruan
AU - Lixin Wan
AU - Dorina Avram
PY - 2026
DA - 2026/09/24
JO - JCI Insight
DO - 10.1172/jci.insight.185437
UR - https://doi.org/10.1172/jci.insight.185437
AB - Ubiquitination is an important posttranslational modification associated with essential cellular processes. Here we show that deletion of E3 ubiquitin ligase HECTD3 — germline or in hematopoietic compartment, including in Cd11c+ cells — causes severe disease and increased production of proinflammatory cytokines in a murine model of ulcerative colitis (UC). HECTD3 mRNA levels were found reduced in colonic tissues of patients with UC, which highlights a potential role for HECTD3 in regulating inflammatory responses in UC. We identified MyD88, a central adaptor in the TLR/IL-1R signaling and inflammatory response, as a target for HECTD3 ubiquitination. We demonstrate that HECTD3 ubiquitinates MyD88 through K27-linked Poly-Ub chains in a nondegradative manner. HECTD3-KO GM-CSF–bone marrow–derived cells treated with the TLR4 ligand LPS produced more proinflammatory cytokines, showed elevated phosphorylation of NF-κB and IRAK4, as well as increased association of MyD88 with IRAK4, demonstrating that HECTD3 controls MyD88/IRAK4/NF-κB axis. Inhibition of MyD88 activity rescued colitis severity in the HECTD3-KO mice, including the elevated proinflammatory cytokine production. Thus, our results establish MyD88 as a target for HECTD3 nondegradative polyubiquitination and restriction of innate immune colonic inflammation.
SN - 2379-3708
ER -