Internalized components of membrane attack complexes disrupt proteostasis and acquire alarmin-like properties

Immune effects of membrane attack complexes (MAC) have been widely attributed to their abilities to cause cell death. Here, we show that the MAC component, C9, forms non-cytolytic aggregates with pro-inflammatory effects. Intracellular aggregates of C9 are detected within inflamed tissues of patients in association with endothelial cell (EC) activation but not increased cell death. We identify NUMBL as a Rab35 effector that directly binds surface-bound C9 to promote C9 internalization and entry into the endolysosomal pathway. Within acidified endolysosomes, C9 forms insoluble aggregates that are targeted for degradative aggrephagy in a process that activates NF-κB. For C9 aggrephagy to occur, ZFYVE21, a Rab5 effector, complexes with RNF34 to bridge C9 aggregates to LC3B+ aggresome membranes. We detect C9 aggregates in vivo, and we show that a ZFYVE21-RNF34 signaling axis is required for C9 aggrephagy and NF-κB -dependent EC activation in three separate mouse models. Mice with conditional loss of ZFYVE21 in ECs show reduced aggregraphy, resulting in attenuated systemic inflammation and reduced tissue injury following skin transplantation. Our data show that the C9 component of MACs forms intracellular aggregates with alarmin-like properties.

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Publication Details

Journal
Nature Communications
Published
2026-07-17
DOI
https://doi.org/10.1038/s41467-026-75696-0
Primary Topic
Cellular transport and secretion
Type
article
Field-Weighted Citation Impact
0.00

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article

Internalized components of membrane attack complexes disrupt proteostasis and acquire alarmin-like properties

Dan Jane‐wit, Quan Jiang, 宋贵玉, George Tellides et al.
Nature Communications
Cellular transport and secretion
article

Internalized components of membrane attack complexes disrupt proteostasis and acquire alarmin-like properties

Dan Jane‐wit, Quan Jiang, 宋贵玉, George Tellides, Li He, Xiangyu Gong, Kamal L. Nahas, Clancy W. Mullan, Qianxun Wang, Matthew Fan, Dylan P. Noone, Andrea Nans, J J Johnson, Doryen Bubeck, Shaoxun Wang, Michael Mak, Pengwei Ren, Mahsa Nouri Barkestani, Zhengtao Jiang, H J Zhou, Zihan Ma, Jolin Cheng, Yinuo Zang, Gilbert Moeckel, Yulong Lan, Weihao Li
article en

Abstract

Immune effects of membrane attack complexes (MAC) have been widely attributed to their abilities to cause cell death. Here, we show that the MAC component, C9, forms non-cytolytic aggregates with pro-inflammatory effects. Intracellular aggregates of C9 are detected within inflamed tissues of patients in association with endothelial cell (EC) activation but not increased cell death. We identify NUMBL as a Rab35 effector that directly binds surface-bound C9 to promote C9 internalization and entry into the endolysosomal pathway. Within acidified endolysosomes, C9 forms insoluble aggregates that are targeted for degradative aggrephagy in a process that activates NF-κB. For C9 aggrephagy to occur, ZFYVE21, a Rab5 effector, complexes with RNF34 to bridge C9 aggregates to LC3B+ aggresome membranes. We detect C9 aggregates in vivo, and we show that a ZFYVE21-RNF34 signaling axis is required for C9 aggrephagy and NF-κB -dependent EC activation in three separate mouse models. Mice with conditional loss of ZFYVE21 in ECs show reduced aggregraphy, resulting in attenuated systemic inflammation and reduced tissue injury following skin transplantation. Our data show that the C9 component of MACs forms intracellular aggregates with alarmin-like properties.

Nature Communications
Peking University (CN), The Francis Crick Institute (GB), Diamond Light Source (GB), Yale University (US), VA Connecticut Research and Education Foundation (US), Peking University People's Hospital (CN), Second Affiliated Hospital of Zhejiang University (CN), Imperial College London (GB), Stony Brook University (US), China Medical University (CN)
U.S. Department of Veterans Affairs, American Federation for Aging Research, American Heart Association, National Heart, Lung, and Blood Institute
Good health and well-being
Openalex Percentile: Top 11%
Cellular transport and secretion
DOIOpen Access PDFOpenAlex
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