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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-\u03baB. For C9 aggrephagy to occur, ZFYVE21, a Rab5 effector, complexes with RNF34 to bridge C9 aggregates to LC3B+ aggresome membranes. We detect C9 aggregates\n                  <jats:italic>in vivo<\/jats:italic>\n                  , and we show that a ZFYVE21-RNF34 signaling axis is required for C9 aggrephagy and NF-\u03baB -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.\n                <\/jats:p>","DOI":"10.64898\/2026.07.03.736247","type":"posted-content","created":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T19:30:18Z","timestamp":1783107018000},"source":"Crossref","is-referenced-by-count":0,"title":["Internalized Components of Membrane Attack Complexes Disrupt Proteostasis and Acquire Alarmin-Like Properties"],"prefix":"10.64898","author":[{"given":"Guiyu","family":"Song","sequence":"first","affiliation":[{"name":"Department of Cardiology, West Haven VA Medical Center, West Haven, CT, USA;"},{"name":"Section of Cardiovascular Medicine, Yale University School of Medicine, New Haven, CT, USA;"},{"name":"Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, 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