Cell Sub-Journal: You Fuping's team reveals a new mechanism of mitochondrial protein involved in antiviral innate immunity

In recent years, more and more research evidence has shown that mitochondria are not only "energy factories", but also play an important role in the immune response.

Mitochondria are at the center of the innate immune response.

First, the key molecules on the mitochondria (such as MAVS) can be used as a signal transmission platform to participate in the anti-RNA virus RLR pathway; second, the mitochondria of eukaryotic cells originate from archaea and therefore have many similar characteristics with bacteria.

Third, studies have reported that mitochondria can release damage-associated molecular patterns (DAMPs), such as mitochondrial DNA and RNA, to activate immune responses.

However, it is rarely reported whether mitochondrial proteins are released to participate in the natural immune response.

RIG-I and MDA5 are the two main receptors for the RLR family to recognize viral RNA, and they are also structurally related: the N-terminal contains two CARD domains in series, the middle is a DECH helicase domain, and a C-terminal.
Structure domain (CTD).

The CTD of the two is quite different in structure, which gives them the ability to sense different viral RNAs.

RIG-I prefers to bind double-stranded RNA (dsRNA) with a triphosphate group at the 5'end, and shorter dsRNA, while MDA5 has a higher affinity for longer dsRNA.

After binding to the viral RNA, RIG-I and MDA5 are recruited to the key adaptor protein MAVS located in the mitochondria.

As a signaling platform, MAVS recruits downstream signaling molecules such as TRAFs, TBK1 and IKK, and activates the kinases TBK1 and IKK.

These kinases further phosphorylate IRF3 and NF-kB, and ultimately promote the expression of downstream antiviral genes.

Although there have been many researches on RIG-I and MDA5 mediated antiviral innate immune signal pathways, there are still many areas to explore about the specific regulatory mechanisms of related signal pathways.

On January 19, 2021, You Fuping team from the Institute of Systems Biomedicine, Peking University Health Science Center published a research paper entitled "The mitochondrial protein ERAL1 suppresses RNA virus infection by facilitating RIG-I-like receptor signaling" in Cell Reports, reporting The mitochondrial protein ERAL1 is involved in the regulation of anti-RNA virus innate immunity.

This study expands the current understanding of the innate immune regulation involved in mitochondrial proteins and reveals that the use of mitochondrial proteins may be an important strategy for regulating innate immune responses.

In this study, the researchers first used the technique of proximity labeling (TurboID) combined with the method of mass spectrometry, and compared the results of the experimental group to find and verify the high-affinity interaction with the mitochondrial outer membrane protein MAVS after Sendai virus (SeV) infection.
Protein ERAL1.

Overexpression of ERAL1 significantly enhanced SeV-induced IFN-β activation.
Consistently, ERAL1 knockdown down-regulated SeV-induced IFN-β activation.

The transcription of downstream antiviral genes induced by RNA virus in Eral1 knockdown mouse macrophages was significantly inhibited, making Eral1-deficient mice more sensitive to vesicular stomatitis virus (VSV)-induced death.

In view of the fact that ERAL1 is located in the mitochondrial matrix in the uninfected state, and MAVS is located in the outer mitochondrial membrane, the researchers speculate that ERAL1 may change its position after virus infection.

Next, through immunofluorescence, immunoelectron microscopy and component separation techniques, the researchers confirmed that ERAL1 can be detected in the cytoplasm after virus infection.

Under stress, mitochondrial outer membrane permeablisation (Mitochondrial outer membrane permeablisation, MOMP) occurs, and mitochondrial proteins are released into the cytoplasm to mediate downstream reactions.

Studies have shown that the Bcl-2 family protein BAX/BAK plays a key role in the occurrence of MOMP.

The release of ERAL1 from the mitochondria to the cytoplasm depends on the BAX/BAK protein, and this process requires the participation of RIG-I and MDA5.

In order to further explore the mechanism of ERAL1's involvement in the antiviral immune response, researchers used proximity labeling technology to find related molecules that may mediate ERAL1 signaling.

Mass spectrometry results show that ERAL1 can interact with TRIM25 in addition to MAVS after virus infection.

TRIM25 is the earliest discovered E3 ubiquitin ligase involved in the activation of ubiquitination at position K63 of RIG-I.

After knocking down ERAL1, viral infection induced a significant down-regulation of the ubiquitination level of RIG-I K63.

In addition, the researchers found that knockdown of ERAL1 also affects the level of virus-induced MDA5 K63 ubiquitination.

In view of the existing studies show that TRIM25 may also mediate the K63-linked polyubiquitination of the CARD domain of MDA5.

The researchers inferred that in the case of viral infection, ERAL1 relies on TRIM25 to enhance the ubiquitination level of RIG-I/MDA5 K63, thereby enhancing the polyubiquitination of MAVS and promoting the antiviral innate immune response.

In conclusion, this study shows that the mitochondrial protein ERAL1 can positively regulate the RLR-mediated innate antiviral immune response.

On the one hand, ERAL1 can bind to MAVS to promote MAVS activation; on the other hand, ERAL1 can be transported from mitochondria to the cytoplasm and promote the K63-linked ubiquitination of RIG-I/MDA5.

This study shows that under viral infection conditions, mitochondria can mediate innate immune responses by releasing proteins, suggesting that mitochondria play an important role in innate immune regulation.

This article was completed by You Fuping's team.
You Fuping's 2016 PhD student Li Siji and 2019 PhD student Kuang Ming are the co-first authors.

You Fuping's research group at Peking University School of Basic Medicine is recruiting postdoctoral fellows for a long time.
Those who are interested, please contact christina_chen@bjmu.
edu.
cn website: http:// Original link: https://doi.
org/ 10.
1016/j.
celrep.
2020.
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