Related Experiment Video

Updated: Jul 19, 2025

In Vitro Analysis of E3 Ubiquitin Ligase Function
06:06

In Vitro Analysis of E3 Ubiquitin Ligase Function

Published on: May 14, 2021

5.3K

MAVS-loaded unanchored Lys63-linked polyubiquitin chains activate the RIG-I-MAVS signaling cascade

Feng Liu1,2, Wanxin Zhuang1,2, Bin Song3

  • 1Key Laboratory of Infection and Immunity of Shandong Province & Key Laboratory for Experimental Teratology of Ministry of Education, Shandong University, Jinan, 250012, Shandong, P.R. China.

Cellular & Molecular Immunology
|August 15, 2023
PubMed

Insights

This study reveals how unanchored K63-linked polyubiquitination of MAVS aggregates regulates RIG-I-like receptor signaling. USP10 deubiquitinase and Ube2N-Riplet/TRIM31 ligase complex control this process, impacting viral defense.

Area of Science:

  • Immunology
  • Molecular Biology
  • Virology

Background:

  • The adaptor protein MAVS aggregates to activate the RIG-I-like receptor (RLR) signaling pathway, crucial for antiviral immunity.
  • Lys63 (K63)-linked polyubiquitination of MAVS is essential for its aggregation, but the specific enzymes involved remain unclear.

Purpose of the Study:

  • To elucidate the mechanism of MAVS aggregation, focusing on the role of K63-linked polyubiquitination.
  • To identify the E3 ligases and deubiquitinating enzymes (DUBs) that regulate MAVS ubiquitination and aggregation.

Main Methods:

  • Investigated the interaction between RIG-I and K63-linked polyubiquitin chains on MAVS.
  • Identified ubiquitin-conjugating enzyme Ube2N, E3 ligases Riplet and TRIM31, and DUB USP10 using biochemical and cellular assays.
  • Assessed the impact of USP10 deficiency on MAVS aggregation, type I interferon production, and viral resistance in mice.

Main Results:

  • RIG-I directly recognizes K63-linked polyubiquitin chains on MAVS, initiating aggregation.
  • Ube2N, Riplet, and TRIM31 collaborate to promote unanchored K63-linked polyubiquitination of MAVS.
  • USP10 deubiquitinates MAVS, attenuating aggregation and type I interferon production; USP10-deficient mice exhibit enhanced resistance to viral infection.

Conclusions:

  • A novel mechanism for RLR signaling activation involves MAVS aggregation mediated by unanchored K63-linked polyubiquitin chains.
  • USP10 acts as a key DUB, while the Ube2N-Riplet/TRIM31 complex serves as the E2:E3 system for regulating MAVS ubiquitination and aggregation during viral infection.
Keywords:
AggregationMAVSRIG-IUSP10Unanchored K63-linked polyubiquitin chains

More Related Videos

Evaluation of Substrate Ubiquitylation by E3 Ubiquitin-ligase in Mammalian Cell Lysates09:47

Evaluation of Substrate Ubiquitylation by E3 Ubiquitin-ligase in Mammalian Cell Lysates

Published on: May 10, 2022

2.6K
Functional Characterization of RING-Type E3 Ubiquitin Ligases In Vitro and In Planta10:27

Functional Characterization of RING-Type E3 Ubiquitin Ligases In Vitro and In Planta

Published on: December 5, 2019

8.9K

Related Concept Videos

Intralumenal Vesicles and Multivesicular Bodies01:38

Intralumenal Vesicles and Multivesicular Bodies

Intraluminal vesicles (ILVs) are small vesicles 50-80 nm in diameter formed during the maturation of early endosomes. A specialized endosome containing numerous ILVs is called a multivesicular body (MVB). ILVs contain internalized molecules such as antigens, nucleic acids, proteins, and metabolites. Some of these molecules are released from the MVBs inside exosomes and are transported to other cells. Other MVBs contain molecules that are retained in the ILVs and are later degraded within the...
3.6K
PI3K/mTOR/AKT Signaling Pathway01:22

PI3K/mTOR/AKT Signaling Pathway

The mammalian target of rapamycin  (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1  (mTORC1) and mTOR complex 2  (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast,  mTORC2 consists of a...
3.7K
Regulation of the Unfolded Protein Response01:31

Regulation of the Unfolded Protein Response

Inositol-requiring kinase one or IRE1 is the most conserved eukaryotic unfolded protein response (UPR) receptor. It is a type I transmembrane protein kinase receptor with a distinctive site-specific RNase activity. As the binding mechanics of the misfolded proteins with the N-terminal domain of IRE-1 are unclear, three binding models — direct, indirect, and allosteric -- are proposed for receptor activation. Nevertheless, it is known that once a misfolded protein associates with IRE1, it...
2.5K
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...
4.7K
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...
7.4K
Receptor Downregulation in MVBs01:15

Receptor Downregulation in MVBs

Multivesicular bodies (MVBs) are mature endosomes that sort ubiquitinated proteins and then fuse with lysosomes to degrade the sorted proteins. Epidermal growth factor (EGF) and its receptor (EGFR) form a complex that can be internalized through endocytosis, sorted into an MVB, and later degraded.
The EGFR can initiate signaling pathways that  lead to cell proliferation, migration, and differentiation. Overexpression of EGFR  stimulates cells to proliferate. Excessive  EGFR...
2.1K