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The C9orf72/SMCR8 complex maintains microglial homeostasis via RAB8A-ESCRT-mediated lysosomal repair.

Overview

Authors: Shan Li1, Shidong Xu1, Feng Li1, Qirui Zhao1, Penghui Zhang1, Qinghua Guan1, Xiangxiang Sun1, Jundong Bi1, Hu Xiao1, Yiyuli Tang1, Cheng Peng1, Qingfeng Chen1, Yonghua Wang1, Mei Yang1
ORCID iDs: Shidong Xu, Xiangxiang Sun, Jundong Bi, Cheng Peng, Qingfeng Chen, Yonghua Wang, Mei Yang
  1. Center for Life Sciences, Yunnan Key Laboratory of Cell Metabolism and Diseases, School of Life Sciences, Yunnan University,Kunming, China
Institutions: Yunnan University (China)
Journal: The EMBO journal, volume 45, issue 13, pages 4531-4568
Dates: received 21 August 2025; accepted 8 May 2026; published online 29 May 2026; in print July 2026
Type: Research article · Language: English
License: CC BY
Identifiers: DOI 10.1038/s44318-026-00817-w · PMID 42215790 · PMCID PMC13324726 · OpenAlex W4413579343
Open access: gold, a free copy (OpenAlex)
Preprint: doi:10.1101/2025.08.22.671707
Status: data only
Categories: human (organism), mouse (organism), cellular / molecular (subfield)
Methods: Statistics, Evoked potentials
Keywords: Membranes & Trafficking, Neuroscience
MeSH: C9orf72 Protein*, Carrier Proteins*, Lysosomes*, Microglia*, rab GTP-Binding Proteins*, Animals, Homeostasis, Humans, Mice, Mice, Knockout (* major topic)
Topic: Adenosine and Purinergic Signaling (Physiology, Biochemistry, Genetics and Molecular Biology), according to OpenAlex
Funding: National Natural Science Foundation of China (National Science Foundation of China) (32070743, 32560156); Yunnan Provincial Science and Technology Department (202401BF070001-015, 202401AS070131, C619300A142); Yunnan University (YNU) (C1762201000139, KC-242410334)
Citations: cited by 1 paper (Europe PMC); 93 references in the paper

Abstract

Microglia are critical regulators of neuroinflammation and neurodegeneration. Haploinsufficiency of C9orf72, the most frequently mutated gene in amyotrophic lateral sclerosis and frontotemporal dementia, has been linked to autophagy-lysosomal pathway defects, but the role of C9orf72 in microglia remains unclear. Here, we identify the C9orf72/SMCR8 complex as a key regulator of microglial homeostasis through promoting lysosomal membrane repair. Loss of C9orf72 and SMCR8 in mice causes age‑dependent neuroinflammation and microgliosis, with microglia adopting a disease-associated state. In aged brain and spinal cord tissue, microglia display lysosomal damage marked by galectin‑3 accumulation. Using a lysosomotropic agent to induce lysosomal damage in microglia, we find that C9orf72/SMCR8-deficient cells accumulate damaged lysosomes and show defective recruitment of phosphorylated RAB8A and the Endosomal Sorting Complexes Required for Transport (ESCRT) machinery to damaged lysosomes. Notably, mutant microglia accumulate GTP‑bound RAB8A, which becomes hyperphosphorylated and mislocalized to RAB7-positive, LAMP1-negative vesicles. The GTPase-activating activity of the C9orf72/SMCR8 complex is essential for lysosomal repair. Our findings reveal that the C9orf72/SMCR8 complex coordinates RAB8A-ESCRT-mediated lysosomal repair to safeguard microglial homeostasis and limit neuroinflammation.

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

Code

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Data

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Data availability

The snRNA-seq reads were deposited in National Genomics Data Center (https://ngdc.cncb.ac.cn) with the BioProject accession number PRJCA055728. Source data for Figs. 1 and EV1 were deposited to BioImage Archive under accession codes S-BSST2788 (http://www.ebi.ac.uk/biostudies/studies/S-BSST2788?key=4c0875e3-bcfc-477c-8119-745e281fd8f5) and S-BSST2792 (http://www.ebi.ac.uk/biostudies/studies/S-BSST2792?key=ed18dcb3-d570-4753-87f5-fa137ca3d673), respectively. Source data for all other figures are available as source data files linked to each figure in the online version of this article.

The source data of this paper are collected in the following database record: biostudies:S-SCDT-10_1038-S44318-026-00817-w (https://www.ebi.ac.uk/biostudies/sourcedata/studies/S-SCDT-10_1038-S44318-026-00817-w).

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, 28 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 14 authors, 2 keywords, 10 MeSH terms, 3 funders, 93 references.

Cite

This paper

Li, S., Xu, S., Li, F., Zhao, Q., Zhang, P., Guan, Q., Sun, X., Bi, J., Xiao, H., Tang, Y., Peng, C., Chen, Q., Wang, Y., & Yang, M. (2026). The C9orf72/SMCR8 complex maintains microglial homeostasis via RAB8A-ESCRT-mediated lysosomal repair. The EMBO journal, 45(13), 4531-4568. https://doi.org/10.1038/s44318-026-00817-w

BibTeX

@article{li2026c9orf72,
author = {Li, Shan and Xu, Shidong and Li, Feng and Zhao, Qirui and Zhang, Penghui and Guan, Qinghua and Sun, Xiangxiang and Bi, Jundong and Xiao, Hu and Tang, Yiyuli and Peng, Cheng and Chen, Qingfeng and Wang, Yonghua and Yang, Mei},
title = {{The C9orf72/SMCR8 complex maintains microglial homeostasis via RAB8A-ESCRT-mediated lysosomal repair}},
journal = {The EMBO journal},
year = {2026},
month = may,
volume = {45},
number = {13},
pages = {4531--4568},
publisher = {Nature Publishing Group},
issn = {0261-4189},
doi = {10.1038/s44318-026-00817-w},
url = {https://doi.org/10.1038/s44318-026-00817-w},
pmid = {42215790},
pmcid = {PMC13324726}
}

RIS

TY - JOUR
AU - Li, Shan
AU - Xu, Shidong
AU - Li, Feng
AU - Zhao, Qirui
AU - Zhang, Penghui
AU - Guan, Qinghua
AU - Sun, Xiangxiang
AU - Bi, Jundong
AU - Xiao, Hu
AU - Tang, Yiyuli
AU - Peng, Cheng
AU - Chen, Qingfeng
AU - Wang, Yonghua
AU - Yang, Mei
TI - The C9orf72/SMCR8 complex maintains microglial homeostasis via RAB8A-ESCRT-mediated lysosomal repair
T2 - The EMBO journal
J2 - EMBO J
PY - 2026
DA - 2026/05/29
VL - 45
IS - 13
SP - 4531
EP - 4568
SN - 0261-4189
PB - Nature Publishing Group
DO - 10.1038/s44318-026-00817-w
UR - https://doi.org/10.1038/s44318-026-00817-w
LA - en
ER -

CSL-JSON

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