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Updated: Jul 12, 2026

Reconstitution of Msp1 Extraction Activity with Fully Purified Components
05:52

Reconstitution of Msp1 Extraction Activity with Fully Purified Components

Published on: August 10, 2021

Internalized Components of Membrane Attack Complexes Disrupt Proteostasis and Acquire Alarmin-Like Properties

Guiyu Song1,2,3, Zihan Ma1,2, Matthew Fan2

  • 1Department of Cardiology, West Haven VA Medical Center, West Haven, CT, USA.

Biorxiv : the Preprint Server for Biology
|July 10, 2026
PubMed

Insights

The complement system's C9 protein forms non-lethal aggregates that trigger inflammation. These intracellular C9 aggregates activate endothelial cells via aggrephagy, promoting inflammatory responses in tissues.

Area of Science:

  • Immunology
  • Cell Biology
  • Molecular Biology

Background:

  • Membrane attack complexes (MAC) are known for causing cell death.
  • The pro-inflammatory roles of MACs, particularly C9, beyond cytolysis are less understood.

Purpose of the Study:

  • To investigate the non-cytolytic functions of C9.
  • To elucidate the mechanisms by which C9 contributes to inflammation.

Main Methods:

  • Detection of intracellular C9 aggregates in patient tissues.
  • Identification of binding partners and pathways involved in C9 internalization and aggrephagy (NUMBL, Rab35, ZFYVE21, RNF34, LC3B).
  • In vivo studies using mouse models to assess the role of ZFYVE21-RNF34 axis in C9 aggrephagy and inflammation.

Main Results:

  • Intracellular C9 aggregates are found in inflamed human tissues, associated with endothelial cell (EC) activation, not cell death.
  • NUMBL mediates C9 internalization into the endolysosomal pathway.
  • C9 aggregates undergo aggrephagy, activating NF-κB via the ZFYVE21-RNF34-LC3B pathway.
  • ZFYVE21-RNF34 signaling is essential for C9 aggrephagy and NF-κB-dependent EC activation in vivo.
  • Conditional ZFYVE21 loss in ECs reduces C9 aggrephagy, systemic inflammation, and tissue injury.

Conclusions:

  • The C9 component of MACs can form intracellular aggregates with alarmin-like properties.
  • C9 aggrephagy is a novel pathway contributing to NF-κB activation and endothelial cell inflammation.
  • Targeting C9 aggrephagy may offer therapeutic strategies for inflammatory diseases.

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