OSCR

OTUB1 non-canonically inhibits TAB2 ubiquitination to govern microglia-mediated neuroinflammation.

Overview

Authors: Zijun Cao1,2, Zhenhu Zhu2, Ping Zeng1,2, Fuqi Mei1, Deqi Wang3, Jun Xu1,2, Yanqi Xu2, Kangmin Chen1, Chushan Wei1,2, Jiangyun Shen2, Keshuo Jin1,2, Jiaqing Chen1,2, Zhongding Li2, Baohua Liu4, Dirk Schlüter5, Jingyong Huang6, Xu Wang1,2,5
ORCID iDs: Fuqi Mei, Jiangyun Shen, Dirk Schlüter, Jingyong Huang, Xu Wang
  1. School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China
  2. Oujiang Laboratory, Zhejiang Lab for Regenerative Medicine, Vision and Brain Health, Wenzhou, China
  3. The First School of Medicine and School of Information and Engineering, Wenzhou Medical University, Wenzhou, China
  4. Department of Rehabilitation, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
  5. Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany
  6. Department of Vascular Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
Institutions: Wenzhou Medical University (China); First Affiliated Hospital of Wenzhou Medical University (China); Medizinische Hochschule Hannover (Germany)
Journal: EMBO molecular medicine, volume 18, issue 8, pages 3137-3156
Dates: received 1 December 2025; accepted 9 June 2026; published online 2 July 2026; in print August 2026
Type: Research article · Language: English
License: CC BY
Identifiers: DOI 10.1038/s44321-026-00473-x · PMID 42393340 · PMCID PMC13470327 · OpenAlex W7167042781
Open access: gold, a free copy (OpenAlex)
Status: data only
Categories: human (organism), mouse (organism), cellular / molecular (subfield)
Methods: Statistics, Smoothing, state filtering, decompositions, Evoked potentials
Keywords: Neuroscience
MeSH: Adaptor Proteins, Signal Transducing*, Cysteine Endopeptidases*, Microglia*, Neuroinflammatory Diseases*, Ubiquitination*, Animals, Encephalomyelitis, Autoimmune, Experimental, Humans, Lipopolysaccharides, Mice, Mice, Inbred C57BL, Mice, Knockout, Signal Transduction, Toll-Like Receptors, Ubiquitin-Conjugating Enzymes (* major topic)
Topic: Ubiquitin and proteasome pathways (Molecular Biology, Biochemistry, Genetics and Molecular Biology), according to OpenAlex
Funding: Oujiang Laboratory (OJQDSP2022014); MOST | NSFC | NSFC-Zhejiang Joint Fund | | Natural Science Foundation of Zhejiang Province (ZJNSF) (LZ24H090003); MOST | National Natural Science Foundation of China (NSFC) (81971143)
Citations: not cited yet (Europe PMC); 61 references in the paper

Abstract

Microglia contribute to detrimental neuroinflammation under pathological conditions and thereby drive the pathogenesis and development of various diseases of the central nervous system (CNS). Here, the deubiquitinating enzyme OTUB1 is identified as a regulator of microglial activation and CNS inflammation. In mice, microglia-specific OTUB1 deletion significantly ameliorates ischemic brain injury by reducing the pro-inflammatory activation of microglia. OTUB1 enhances Toll-like receptor (TLR) signaling through stabilizing UBC13 and TAB2, leading to the increased induction of cytokines. Notably, OTUB1 reduces the proteasomal degradation of TAB2 by reducing its K48 ubiquitination in a catalytic activity-independent manner. Moreover, microglia-confined OTUB1 deficiency also alleviates lipopolysaccharide-induced sickness behavior and experimental autoimmune encephalomyelitis in mice due to decreased neuroinflammation. Pharmacological inhibition of OTUB1 significantly mitigated ischemic stroke injury in mice. These findings reveal an important role of OTUB1 in potentiating microglial activation and neuroinflammation, providing a proof-of-principle observation for targeting OTUB1 in the treatment of TLR-associated neuroinflammatory diseases.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Data

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Data availability

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The source data of this paper are collected in the following database record: biostudies:S-SCDT-10_1038-S44321-026-00473-x (https://www.ebi.ac.uk/biostudies/sourcedata/studies/S-SCDT-10_1038-S44321-026-00473-x).

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.

Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 17 authors, 1 keyword, 15 MeSH terms, 3 funders, 61 references.

Cite

This paper

Cao, Z., Zhu, Z., Zeng, P., Mei, F., Wang, D., Xu, J., Xu, Y., Chen, K., Wei, C., Shen, J., Jin, K., Chen, J., Li, Z., Liu, B., Schlüter, D., Huang, J., & Wang, X. (2026). OTUB1 non-canonically inhibits TAB2 ubiquitination to govern microglia-mediated neuroinflammation. EMBO molecular medicine, 18(8), 3137-3156. https://doi.org/10.1038/s44321-026-00473-x

BibTeX

@article{cao2026otub1,
author = {Cao, Zijun and Zhu, Zhenhu and Zeng, Ping and Mei, Fuqi and Wang, Deqi and Xu, Jun and Xu, Yanqi and Chen, Kangmin and Wei, Chushan and Shen, Jiangyun and Jin, Keshuo and Chen, Jiaqing and Li, Zhongding and Liu, Baohua and Schlüter, Dirk and Huang, Jingyong and Wang, Xu},
title = {{OTUB1 non-canonically inhibits TAB2 ubiquitination to govern microglia-mediated neuroinflammation}},
journal = {EMBO molecular medicine},
year = {2026},
month = jul,
volume = {18},
number = {8},
pages = {3137--3156},
publisher = {Nature Publishing Group},
issn = {1757-4676},
doi = {10.1038/s44321-026-00473-x},
url = {https://doi.org/10.1038/s44321-026-00473-x},
pmid = {42393340},
pmcid = {PMC13470327}
}

RIS

TY - JOUR
AU - Cao, Zijun
AU - Zhu, Zhenhu
AU - Zeng, Ping
AU - Mei, Fuqi
AU - Wang, Deqi
AU - Xu, Jun
AU - Xu, Yanqi
AU - Chen, Kangmin
AU - Wei, Chushan
AU - Shen, Jiangyun
AU - Jin, Keshuo
AU - Chen, Jiaqing
AU - Li, Zhongding
AU - Liu, Baohua
AU - Schlüter, Dirk
AU - Huang, Jingyong
AU - Wang, Xu
TI - OTUB1 non-canonically inhibits TAB2 ubiquitination to govern microglia-mediated neuroinflammation
T2 - EMBO molecular medicine
J2 - EMBO Mol Med
PY - 2026
DA - 2026/07/02
VL - 18
IS - 8
SP - 3137
EP - 3156
SN - 1757-4676
PB - Nature Publishing Group
DO - 10.1038/s44321-026-00473-x
UR - https://doi.org/10.1038/s44321-026-00473-x
LA - en
ER -

CSL-JSON

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"issued": {
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