MAVI1, an Endoplasmic Reticulum-localized Microprotein, Suppresses Antiviral Innate Immune Response by Targeting MAVS on Mitochondrion

Overview

Journal Sci Adv

Specialties Biology
Science

Date 2023 Sep 1

PMID 37656786

Authors

Tao-Tao Shi

Ying Huang

Ying Li

Xiang-Long Dai

Yao-Hui He

Jian-Cheng Ding

Ting Ran

Yang Shi

Quan Yuan

Wen-Juan Li

Wen Liu

Affiliations

Soon will be listed here.

Abstract

Pattern recognition receptor-mediated innate immunity is critical for host defense against viruses. A growing number of coding and noncoding genes are found to encode microproteins. However, the landscape and functions of microproteins in responsive to virus infection remain uncharacterized. Here, we systematically identified microproteins that are responsive to vesicular stomatitis virus infection. A conserved and endoplasmic reticulum-localized membrane microprotein, MAVI1 (microprotein in antiviral immunity 1), was found to interact with mitochondrion-localized MAVS protein and inhibit MAVS aggregation and type I interferon signaling activation. The importance of MAVI1 was highlighted that viral infection was attenuated and survival rate was increased in knockout mice. A peptide inhibitor targeting the interaction between MAVI1 and MAVS activated the type I interferon signaling to defend viral infection. Our findings uncovered that microproteins play critical roles in regulating antiviral innate immune responses, and targeting microproteins might represent a therapeutic avenue for treating viral infection.

Citing Articles

Nucleotide coordinated polymers, a ROS-based immunomodulatory antimicrobial, doubly kill biofilms of implant infections.

Chen J, Tang X, Sun Q, Ji X, Wang X, Liu Z Bioact Mater. 2024; 44:461-473.

PMID: 39559424 PMC: 11570693. DOI: 10.1016/j.bioactmat.2024.10.026.

Targeting PRMT7-mediated monomethylation of MAVS enhances antiviral innate immune responses and inhibits RNA virus replication.

Yang J, Li W, Zhang Z, Gong X, Chen Y, Peng X Proc Natl Acad Sci U S A. 2024; 121(47):e2408117121.

PMID: 39546576 PMC: 11588101. DOI: 10.1073/pnas.2408117121.

Microproteins in cancer: identification, biological functions, and clinical implications.

Hofman D, Prensner J, van Heesch S Trends Genet. 2024; 41(2):146-161.

PMID: 39379206 PMC: 11794034. DOI: 10.1016/j.tig.2024.09.002.

Small but mighty: the rise of microprotein biology in neuroscience.

Duffy E, Assad E, Kalish B, Greenberg M Front Mol Neurosci. 2024; 17:1386219.

PMID: 38807924 PMC: 11130481. DOI: 10.3389/fnmol.2024.1386219.

Noncanonical microprotein regulation of immunity.

Nichols C, Do-Thi V, Peltier D Mol Ther. 2024; 32(9):2905-2929.

PMID: 38734902 PMC: 11403233. DOI: 10.1016/j.ymthe.2024.05.021.

References

DLima N, Ma J, Winkler L, Chu Q, Loh K, Corpuz E . A human microprotein that interacts with the mRNA decapping complex. Nat Chem Biol. 2016; 13(2):174-180. PMC: 5247292. DOI: 10.1038/nchembio.2249. View

Seth R, Sun L, Ea C, Chen Z . Identification and characterization of MAVS, a mitochondrial antiviral signaling protein that activates NF-kappaB and IRF 3. Cell. 2005; 122(5):669-82. DOI: 10.1016/j.cell.2005.08.012. View

Mellacheruvu D, Wright Z, Couzens A, Lambert J, St-Denis N, Li T . The CRAPome: a contaminant repository for affinity purification-mass spectrometry data. Nat Methods. 2013; 10(8):730-6. PMC: 3773500. DOI: 10.1038/nmeth.2557. View

Gao W, Xiao R, Zhang W, Hu Y, Peng B, Li W . JMJD6 Licenses ERα-Dependent Enhancer and Coding Gene Activation by Modulating the Recruitment of the CARM1/MED12 Co-activator Complex. Mol Cell. 2018; 70(2):340-357.e8. PMC: 6258263. DOI: 10.1016/j.molcel.2018.03.006. View

Szabadkai G, Bianchi K, Varnai P, De Stefani D, Wieckowski M, Cavagna D . Chaperone-mediated coupling of endoplasmic reticulum and mitochondrial Ca2+ channels. J Cell Biol. 2006; 175(6):901-11. PMC: 2064700. DOI: 10.1083/jcb.200608073. View

Yang J, Zhong W, Li J, Lin Y, Liu F, Tian H . LINC00998-encoded micropeptide SMIM30 promotes the G1/S transition of cell cycle by regulating cytosolic calcium level. Mol Oncol. 2022; 17(5):901-916. PMC: 10158777. DOI: 10.1002/1878-0261.13358. View

Cai H, Yu Y, Ni X, Li C, Hu Y, Wang J . LncRNA LINC00998 inhibits the malignant glioma phenotype via the CBX3-mediated c-Met/Akt/mTOR axis. Cell Death Dis. 2020; 11(12):1032. PMC: 7710718. DOI: 10.1038/s41419-020-03247-6. View

Williamson C, Wong D, Bozidis P, Zhang A, Colberg-Poley A . Isolation of Endoplasmic Reticulum, Mitochondria, and Mitochondria-Associated Membrane and Detergent Resistant Membrane Fractions from Transfected Cells and from Human Cytomegalovirus-Infected Primary Fibroblasts. Curr Protoc Cell Biol. 2015; 68:3.27.1-3.27.33. PMC: 4607254. DOI: 10.1002/0471143030.cb0327s68. View

Dias Junior A, Sampaio N, Rehwinkel J . A Balancing Act: MDA5 in Antiviral Immunity and Autoinflammation. Trends Microbiol. 2018; 27(1):75-85. PMC: 6319154. DOI: 10.1016/j.tim.2018.08.007. View

10.

Hayashi T, Rizzuto R, Hajnoczky G, Su T . MAM: more than just a housekeeper. Trends Cell Biol. 2009; 19(2):81-8. PMC: 2750097. DOI: 10.1016/j.tcb.2008.12.002. View

11.

Rodriguez-Morales A, Bonilla-Aldana D, Balbin-Ramon G, Rabaan A, Sah R, Paniz-Mondolfi A . History is repeating itself: Probable zoonotic spillover as the cause of the 2019 novel Coronavirus Epidemic. Infez Med. 2020; 28(1):3-5. View

12.

Parimoo S, Rao N, Padmanaban G . Cytochrome c oxidase is preferentially synthesized in the rough endoplasmic reticulum--mitochondrion complex in rat liver. Biochem J. 1982; 208(2):505-7. PMC: 1153990. DOI: 10.1042/bj2080505. View

13.

Lewis S, Uchiyama L, Nunnari J . ER-mitochondria contacts couple mtDNA synthesis with mitochondrial division in human cells. Science. 2016; 353(6296):aaf5549. PMC: 5554545. DOI: 10.1126/science.aaf5549. View

14.

Vance J . Phospholipid synthesis in a membrane fraction associated with mitochondria. J Biol Chem. 1990; 265(13):7248-56. View

15.

Moore C, Bergstralh D, Duncan J, Lei Y, Morrison T, Zimmermann A . NLRX1 is a regulator of mitochondrial antiviral immunity. Nature. 2008; 451(7178):573-7. DOI: 10.1038/nature06501. View

16.

Xu L, Wang Y, Han K, Li L, Zhai Z, Shu H . VISA is an adapter protein required for virus-triggered IFN-beta signaling. Mol Cell. 2005; 19(6):727-40. DOI: 10.1016/j.molcel.2005.08.014. View

17.

Chen Y, Kim M, Chen X, Batista P, Aoyama S, Wilusz J . Sensing Self and Foreign Circular RNAs by Intron Identity. Mol Cell. 2017; 67(2):228-238.e5. PMC: 5610545. DOI: 10.1016/j.molcel.2017.05.022. View

18.

Anderson D, Anderson K, Chang C, Makarewich C, Nelson B, McAnally J . A micropeptide encoded by a putative long noncoding RNA regulates muscle performance. Cell. 2015; 160(4):595-606. PMC: 4356254. DOI: 10.1016/j.cell.2015.01.009. View

19.

Cai C, Tang Y, Xu G, Zheng C . The crosstalk between viral RNA- and DNA-sensing mechanisms. Cell Mol Life Sci. 2021; 78(23):7427-7434. PMC: 8554519. DOI: 10.1007/s00018-021-04001-7. View

20.

Meng N, Chen M, Chen D, Chen X, Wang J, Zhu S . Small Protein Hidden in lncRNA Promotes "Cancerous" RNA Splicing and Tumorigenesis. Adv Sci (Weinh). 2020; 7(10):1903233. PMC: 7237858. DOI: 10.1002/advs.201903233. View