Autophagy supports genomic stability by degrading retrotransposon RNA

Abstract

Many cytoplasmic substrates degraded by autophagy have been identified; however, the impact of RNA degradation by autophagy remains uncertain. Retrotransposons comprise 40% of the human genome and are a major source of genetic variation among species, individuals and cells. Retrotransposons replicate via a copy-paste mechanism involving a cytoplasmic RNA intermediate. Here we report that autophagy degrades retrotransposon RNA from both long and short interspersed elements, preventing new retrotransposon insertions into the genome. Retrotransposon RNA localizes to RNA granules, whose selective degradation is facilitated by the autophagy receptors NDP52 and p62. Accordingly, NDP52 and p62 control retrotransposon insertion in the genome. Mice lacking a copy of Atg6/Beclin1, a gene critical for autophagy, also accumulate both retrotransposon RNA and genomic insertions. Thus, autophagy physiologically buffers genetic variegation by degrading retrotransposon RNA. This may contribute to the increased tumorigenesis occuring when autophagy is inhibited and suggest a role for autophagy in tempering evolutionary change.

Ubiquitin-Dependent And Independent Signals In Selective Autophagy

“…Disused or aberrantly folded proteins are tagged with Ub signals that are subsequently sensed by UBD (Ub binding domain)-containing receptors to deliver them to the proteasome or the autophagosome during autophagy [26,31] (Figure 2). Similarly to the role of shuttling factors and proteasomal receptors in recognizing ubiquitinated substrates, autophagy relies on its own arsenal of autophagy receptors to recognize intracellular ubiquitinated aggregates (p62, NBR1, OPTN, TOLLIP) [32][33][34][35][36], bacteria (p62, OPTN, NDP52) [37][38][39], peroxisomes (NBR1) [40], mitochondria (OPTN, NDP52, Tax1BP1) [41][42][43], zymogen particles (p62) [16], proteasome (RPN10) [24], midbody (p62, NBR1) [15,44], or nucleic acids (p62, NDP52) [18,45] (Table 1), and link the material to autophagosomal membranes. Notably, the capacity of ubiquitinated proteins to form aggregates, and thus become autophagy substrates, has been shown to depend on Ub chain length [46].…”

Retrotransposons as regulators of gene expression

“…Microprocessor, a nuclear complex of miRNA-processing enzymes, also recognizes and cleaves L1, Alu , and SVA transcripts, at least in vitro (97). The finding that L1 and Alu RNAs are enclosed within human cell autophagosomes has implicated autophagy (i.e., the delivery of cytosolic constituents to the lysosome) as another host defense mechanism that degrades retrotransposon RNAs (98). Indeed, mice lacking the critical autophagy gene, Atg6/Beclin1, are characterized by higher levels of retrotransposon RNAs and increased rates of genomic insertions (98).…”

“…The finding that L1 and Alu RNAs are enclosed within human cell autophagosomes has implicated autophagy (i.e., the delivery of cytosolic constituents to the lysosome) as another host defense mechanism that degrades retrotransposon RNAs (98). Indeed, mice lacking the critical autophagy gene, Atg6/Beclin1, are characterized by higher levels of retrotransposon RNAs and increased rates of genomic insertions (98). Additionally, retrotransposition is restricted in both somatic and germ cells by members of the apolipoprotein B mRNA-editing enzyme 3 (APOBEC3) family (89, 99).…”

Role of RN Autophagy Mediated ERV Suppression in Cellular Senescence

“…Autophagy mainly consist of three types namely, micro, macro and chaperone mediated. Recent studies suggested the fourth autophagic mechanism, RNautophagy, to degrade retrotransposon RNA [18][19][20] related proteins-LAMP2B, SIDT2 were suppressed at 4 days post senescence, while were significantly upregulated in 12 days post senescence ( Figure 3A).…”