# Complement Membrane Attack Complexes Disrupt Proteostasis to Function as Intracellular Alarmins

## TL;DR

This study reveals that membrane attack complexes (MACs) can disrupt protein balance inside cells, leading to inflammation and tissue damage.

## Contribution

The novel finding is that MACs, particularly C9, form aggregates that act as intracellular alarmins, triggering inflammation via proteostasis disruption.

## Key findings

- C9 aggregates in Rab5+ endosomes trigger aggrephagy and NF-kB activation.
- ZFYVE21 links LC3A/B to RNF34-P62 complexes to mediate C9 aggrephagy.
- Mice lacking ZFYVE21 in endothelial cells show reduced MAC-induced tissue injury.

## Abstract

Internalized pools of membrane attack complexes (MACs) promote NF-kB and dysregulated tissue inflammation. Here, we show that C9, a MAC-associated protein, promotes loss of proteostasis to become intrinsically immunogenic. Surface-bound C9 is internalized into Rab5 + endosomes whose intraluminal acidification promotes C9 aggregates. A region within the MACPF/CDC domain of C9 stimulates aggrephagy to induce NF-kB, inflammatory genes, and EC activation. This process requires ZFYVE21, a Rab5 effector, which links LC3A/B on aggresome membranes to RNF34-P62 complexes to mediate C9 aggrephagy. C9 aggregates form in human tissues, C9-associated signaling responses occur in three mouse models, and ZFYVE21 stabilizes RNF34 to promote C9 aggrephagy in vivo. Gene-deficient mice lacking ZFYVE21 in ECs showed reduced MAC-induced tissue injury in a skin model of chronic rejection. While classically defined as cytotoxic effectors, MACs may impair proteostasis, forming aggregates that behave as intracellular alarmins.