Caenorhabditis elegans ADAR editing and the ERI-6/7/MOV10 RNAi pathway silence endogenous viral elements and LTR retrotransposons

Abstract

Endogenous retroviruses and long terminal repeat (LTR) retrotransposons are mobile genetic elements that are closely related to retroviruses. Desilenced endogenous retroviruses are associated with human autoimmune disorders and neurodegenerative diseases. Caenorhabditis elegans and related Caenorhabditis spp. contain LTR retrotransposons and, as described here, numerous integrated viral genes including viral envelope genes that are part of LTR retrotransposons. We found that both LTR retrotransposons and endogenous viral elements are silenced by ADARs [adenosine deaminases acting on double-stranded RNA (dsRNA)] together with the endogenous RNA interference (RNAi) factor ERI-6/7, a homolog of MOV10 helicase, a retrotransposon and retrovirus restriction factor in human. siRNAs corresponding to integrated viral genes and LTR retrotransposons, but not to DNA transposons, are dependent on the ADARs and ERI-6/7. siRNAs corresponding to palindromic repeats are independent of the ADARs and ERI-6/7, and are in fact increased in adarand eri-6/7-defective mutants because of an antiviral RNAi response to dsRNA. Silencing of LTR retrotransposons is dependent on downstream RNAi factors and P granule components but is independent of the viral sensor DRH-1/ RIG-I and the nuclear Argonaute NRDE-3. The activation of retrotransposons in the ADAR-and ERI-6/7/MOV10-defective mutant is associated with the induction of the unfolded protein response (UPR), a common response to viral infection. The overlap between genes induced upon viral infection and infection with intracellular pathogens and genes coexpressed with retrotransposons suggests that there is a common response to different types of foreign elements that includes a response to proteotoxicity presumably caused by the burden of replicating pathogens and expressed retrotransposons.RNA interference | ADAR | retrotransposon | RNA silencing

Mitochondrial dysfunction induces RNA interference in C. elegans through a pathway homologous to the mammalian RIG-I antiviral response

“…In mammalian cells, the RNA helicase MDA5 mediates an interferon antiviral immune response that is strongly enhanced by a mitochondrial RNA degradation mutation that enhances production of mitochondrial dsRNAs [25]. Intriguingly, mutations in the C. elegans homologue of MDA5, drh-1, suppress the synthetic lethality of Eri and dsRNA editing double mutants [21,42]. C. elegans DRH-1 contains 3 domains, including conserved helicase domain and C-terminal domain (CTD) ( Fig 1F) and an N-terminal domain (NTD) that is only conserved in nematodes (S1A Fig).…”

“…The eol-1 RNA decapping gene was also strongly induced in virally infected and mitochondrial mutant C. elegans (S1 Table). We selected eol-1 for detailed analysis because (1) it is conserved from yeast to mammals ( Fig 2B); (2) eol-1 expression is induced by multiple mitochondrial mutations as well as in a eri-6i, adr-1/2 Eri mutant that desilences endogenous retroviruses and retrotransposons [21,44]; (3) the induction of eol-1 by Orsay virus infection is dependent on drh-1 [45]; and (4) the human orthologue of EOL-1, DXO, represses hepatitis C virus replication [46]. C. elegans eol-1 was initially identified as a mutant that enhanced olfactory learning after Pseudomonas aeruginosa infection [47].…”

“…The RNAi pathway drives gene silencing of mRNAs that have signatures of being foreign. For example, many of the Eri mutants mediate the silencing of integrated viruses in the C. elegans genome that are recently acquired [21]. These viral genes are recognized as foreign by their small number of introns, for example, and by poor splice sites [68].…”

“…But the Argonaute and RdRP gene families are expanded in C. elegans compared with most animals, and surprisingly, loss-of-function mutations in some of those genes causes an increase in the response to siRNAs: mutations in the RdRP RRF-3, the specialized Argonaute ERGO-1, the RNA helicase ERI-6/7, or the exoribonuclease ERI-1 enhance silencing by siRNAs [19,20]. Many of these enhanced RNAi (Eri) mutations desilence retroviral elements in the C. elegans genome so that antiviral response pathways are triggered to in turn induce the expression of RNAi-based antiviral defense [21].…”

“…Many of these enhanced RNAi (Eri) mutations desilence retroviral elements in the C . elegans genome so that antiviral response pathways are triggered to in turn induce the expression of RNAi-based antiviral defense [ 21 ].…”