Related Experiment Video

Updated: Jun 22, 2025

Detection of Inflammasome Activation and Pyroptotic Cell Death in Murine Bone Marrow-derived Macrophages
06:52

Detection of Inflammasome Activation and Pyroptotic Cell Death in Murine Bone Marrow-derived Macrophages

Published on: May 21, 2018

10.7K

Complement Membrane Attack Complexes Disrupt Proteostasis to Function as Intracellular Alarmins

Dan Jane-Wit1, Guiyu Song2, Liying He1

  • 1Yale University.

Research Square
|July 1, 2024
PubMed

Insights

Membrane attack complexes (MACs) internalize, forming aggregates that trigger inflammation. This process involves C9 protein, aggrephagy, and ZFYVE21, revealing MACs as intracellular alarmins.

Area of Science:

  • Immunology
  • Cell Biology
  • Molecular Biology

Background:

  • Membrane attack complexes (MACs) are known to cause cell lysis.
  • Internalized MACs are implicated in NF-kB activation and tissue inflammation.

Purpose of the Study:

  • To investigate the role of C9, a MAC-associated protein, in proteostasis and immune signaling.
  • To elucidate the mechanism by which C9 aggregates induce inflammatory responses.

Main Methods:

  • Utilized cell culture models and mouse models.
  • Investigated protein aggregation, endocytosis, and aggrephagy pathways.
  • Employed gene-deficient mice to study the role of ZFYVE21.

Main Results:

  • Surface-bound C9 is internalized, aggregated within endosomes, and promotes loss of proteostasis.
  • C9 aggregates stimulate NF-kB, inflammatory genes, and endothelial cell activation via aggrephagy.
  • ZFYVE21 is crucial for C9 aggrephagy and stabilization of RNF34, impacting tissue injury.

Conclusions:

  • C9 aggregates act as intracellular alarmins, linking MACs to inflammation beyond cytotoxicity.
  • The C9-mediated aggrephagy pathway involving ZFYVE21 is a novel mechanism of immune activation.
  • Targeting this pathway may offer therapeutic strategies for inflammatory diseases.

Keywords:
RNF34Rab5ZFYVE21aggrephagyalarmincomplementendosomeendothelial cellmacroautophagymembrane attack complex

More Related Videos

Activation and Measurement of NLRP3 Inflammasome Activity Using IL-1β in Human Monocyte-derived Dendritic Cells09:04

Activation and Measurement of NLRP3 Inflammasome Activity Using IL-1β in Human Monocyte-derived Dendritic Cells

Published on: May 22, 2014

20.9K
Myeloid Innate Signaling Pathway Regulation by MALT1 Paracaspase Activity07:09

Myeloid Innate Signaling Pathway Regulation by MALT1 Paracaspase Activity

Published on: January 7, 2019

7.5K

Related Concept Videos

Complement System01:27

Complement System

The complement system is a group of approximately 20 plasma proteins that strengthen the body's defenses against infections through opsonization, inflammation, and cell lysis. Opsonization involves coating pathogens with complement proteins, making them more recognizable and facilitating phagocyte engulfment. Certain complement proteins induce inflammation that attracts immune cells to the site of infection. Cell lysis involves the destruction of pathogens through the formation of a...
2.3K
The Unfolded Protein Response01:37

The Unfolded Protein Response

The ER is the hub of protein synthesis in a cell. It has robust systems to quality control protein folding and also for degradation of terminally misfolded proteins. Under normal conditions, a small proportion of misfolded proteins that cannot be salvaged need to be transported to the cytoplasm by the ER-associated degradation or ERAD pathways. However, if the ERAD cannot handle the misfolded proteins, the cell activates the unfolded protein response or UPR to adjust the protein folding...
4.5K
Antimicrobial Proteins01:23

Antimicrobial Proteins

Antimicrobial proteins are important components of the immune system. They aid the body in combating pathogens by either killing them directly or hindering their replication processes. Four main types of antimicrobial substances are interferons, the complement system, iron-binding proteins, and antimicrobial proteins.
Interferons
Interferons (IFNs) are proteins produced by lymphocytes, macrophages, and fibroblasts infected with viruses. While IFNs cannot prevent viruses from entering and...
975
The Intrinsic Apoptotic Pathway01:31

The Intrinsic Apoptotic Pathway

Internal cellular stress, such as cellular injury or hypoxia, triggers intrinsic apoptosis. The B-cell lymphoma 2 (Bcl-2) family of proteins are the primary regulators of the intrinsic apoptotic pathway. For example, during DNA damage, checkpoint proteins, such as Ataxia Telangiectasia Mutated (ATM protein) and Checkpoints Factor-2 (Chk2) proteins, are activated. These proteins phosphorylate p53 which further activates pro-apoptotic proteins, such as Bax, Bak, PUMA, and Noxa, and inhibits...
6.5K
Regulated Protein Degradation02:58

Regulated Protein Degradation

It is vital to regulate the activity of enzymatic as well as non-enzymatic proteins inside the cell. This can be achieved either through creating a balance between their rate of synthesis and degradation or regulating the intrinsic activity of the protein. Both these regulation mechanisms play an essential role in the normal functioning of cells.
Protein degradation plays two important roles in the cells. It helps to protect cells from misfolded or damaged proteins before they lead to a...
7.2K
The Extrinsic Apoptotic Pathway01:17

The Extrinsic Apoptotic Pathway

The extrinsic apoptotic pathway is initiated when extracellular death-inducing signals, such as specific cytokines, activate the death receptors expressed on the cell surface. The immune cells involved in this pathway are natural killer cells (NK cells) and cytotoxic T-lymphocytes. NK cells are critical in innate immune response, while cytotoxic T-lymphocytes are associated with adaptive immune response. These cells recognize specific receptors expressed on the altered cells and activate...
6.3K