ZCCHC3 is a stress granule zinc knuckle protein that strongly suppresses LINE-1 retrotransposition

Retrotransposons have generated about half of the human genome and LINE-1s (L1s) are the only autonomously active retrotransposons. The cell has evolved an arsenal of defense mechanisms to protect against retrotransposition with factors we are only beginning to understand. In this study, we investig...

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Bibliographic Details
Published in:	PLoS genetics Vol. 19; no. 7; p. e1010795
Main Authors:	Goodier, John L, Wan, Han, Soares, Alisha O, Sanchez, Laura, Selser, John Michael, Pereira, Gavin C, Karma, Sadik, García-Pérez, José Luis, Kazazian, Jr, Haig H, García Cañadas, Marta M
Format:	Journal Article
Language:	English
Published:	United States Public Library of Science 05-07-2023
Subjects:	Analysis Antibodies Antiviral agents Biology and Life Sciences Cell culture Centrifugation DNA binding proteins DNA helicase Gag protein Genetic translation Genomes Genomics Heat-Shock Proteins - genetics Humans Identification and classification Immune response Immunoprecipitation Innate immunity Localization Long interspersed nucleotide elements Long Interspersed Nucleotide Elements - genetics Properties Proteins Research and analysis methods Retroelements - genetics Retrotransposition Ribonuclease RNA RNA helicase RNA Helicases - genetics RNA Helicases - metabolism Scientific equipment and supplies industry Stress Granules Translation initiation Transposons Viruses Zinc Zinc finger proteins United States
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Summary:	Retrotransposons have generated about half of the human genome and LINE-1s (L1s) are the only autonomously active retrotransposons. The cell has evolved an arsenal of defense mechanisms to protect against retrotransposition with factors we are only beginning to understand. In this study, we investigate Zinc Finger CCHC-Type Containing 3 (ZCCHC3), a gag-like zinc knuckle protein recently reported to function in the innate immune response to infecting viruses. We show that ZCCHC3 also severely restricts human retrotransposons and associates with the L1 ORF1p ribonucleoprotein particle. We identify ZCCHC3 as a bona fide stress granule protein, and its association with LINE-1 is further supported by colocalization with L1 ORF1 protein in stress granules, dense cytoplasmic aggregations of proteins and RNAs that contain stalled translation pre-initiation complexes and form when the cell is under stress. Our work also draws links between ZCCHC3 and the anti-viral and retrotransposon restriction factors Mov10 RISC Complex RNA Helicase (MOV10) and Zinc Finger CCCH-Type, Antiviral 1 (ZC3HAV1, also called ZAP). Furthermore, collective evidence from subcellular localization, co-immunoprecipitation, and velocity gradient centrifugation connects ZCCHC3 with the RNA exosome, a multi-subunit ribonuclease complex capable of degrading various species of RNA molecules and that has previously been linked with retrotransposon control.
Bibliography:	new_version ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 The authors have declared that no competing interests exist.
ISSN:	1553-7404 1553-7390 1553-7404
DOI:	10.1371/journal.pgen.1010795