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Review
. 2017 Jan 2;13(1):3-23.
doi: 10.1080/15548627.2016.1222992. Epub 2016 Oct 7.

Emerging connections between RNA and autophagy

Affiliations
Review

Emerging connections between RNA and autophagy

Lisa B Frankel et al. Autophagy. .

Abstract

Macroautophagy/autophagy is a key catabolic process, essential for maintaining cellular homeostasis and survival through the removal and recycling of unwanted cellular material. Emerging evidence has revealed intricate connections between the RNA and autophagy research fields. While a majority of studies have focused on protein, lipid and carbohydrate catabolism via autophagy, accumulating data supports the view that several types of RNA and associated ribonucleoprotein complexes are specifically recruited to phagophores (precursors to autophagosomes) and subsequently degraded in the lysosome/vacuole. Moreover, recent studies have revealed a substantial number of novel autophagy regulators with RNA-related functions, indicating roles for RNA and associated proteins not only as cargo, but also as regulators of this process. In this review, we discuss widespread evidence of RNA catabolism via autophagy in yeast, plants and animals, reviewing the molecular mechanisms and biological importance in normal physiology, stress and disease. In addition, we explore emerging evidence of core autophagy regulation mediated by RNA-binding proteins and noncoding RNAs, and point to gaps in our current knowledge of the connection between RNA and autophagy. Finally, we discuss the pathological implications of RNA-protein aggregation, primarily in the context of neurodegenerative disease.

Keywords: RNA degradation; RNA-binding proteins; autophagy; granulophagy; noncoding RNA; ribophagy.

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Figures

Figure 1.
Figure 1.
An overview of RNA-autophagy crosstalk in eukaryotic cells. The autophagy pathway degrades several different types of RNA and ribonucleoprotein complexes. RNAs and RNA-binding proteins (RBPs) can also act as regulators of the autophagy process. (A) Cytoplasmic RNA granules such as stress granules (SG) and processing-bodies (PB) are recruited to the autophagosome via SQSTM1 and CALCOCO2 receptors in the process of granulophagy. RNAs targeted for autophagic degradation via granulophagy include mRNAs and retrotransposon RNAs LINE 1 and Alu. VCP, or the yeast homolog Cdc48, are mediators of granulophagy. (B) LC3B can bind directly to RNA, although the significance of this with regard to autophagy is unknown. (C) During ribophagy, small (40S) and large (60S) ribosomal subunits are selectively recruited to the phagophore. In yeast, the mechanism for 60S recruitment involves de-ubiquitination via the Ubp3-Bre5 complex, whereas mechanisms for 40S recruitment remain unclear. (D) Aggrephagy involves selective recruitment of protein-RNA aggregates to phagophores. Disease-related aggregate-prone RNA-binding proteins include TARDBP and FUS. (E) RNA viruses can utilize phagophore and/or autophagosome membranes as viral replication hubs. RNA viruses can also be selectively degraded by xenophagy. (F) RNA degradation in the vacuole/lysosome can occur via the RNASET2 family. Additional recruitment of RNA directly to the lysosome may occur via an RNA-binding domain in the cytosolic region of the lysosomal membrane protein LAMP2C. (G) ATG mRNAs can be post-transcriptionally regulated by a large cohort of RNA-binding proteins and noncoding RNAs including microRNAs (miRNAs) and long noncoding RNAs (lncRNAs) (see text for details).
Figure 2.
Figure 2.
RNA degradation in the vacuole/lysosome. tRNA, rRNA and likely additional types of RNA (RNA X) are degraded in vacuoles/lysosomes by the RNASET2 family. The yeast RNase T2, Rny1, cleaves RNA to 3′ nucleotide monophosphates (3′NMPs), which are further converted to nucleosides by the vacuolar phosphatase Pho8. Both Rny1 and Pho8 expression levels are increased by starvation. Nucleosides are exported from the vacuole to the cytoplasm where Pnp1 and Urh1 further process them into nucleobases. Through as yet unknown mechanisms, nucleobases can be excreted from yeast cells. LAMP2C may mediate direct import of RNA to lysosomes through an ATP-dependent mechanism (see text for details).
Figure 3.
Figure 3.
Mechanisms of ribophagy in yeast. Ubiquitin ligases identified to have an impact on ribophagy include Rsp5 and Rkr1/Ltn1. Expression of Rkr1 is inhibited by nitrogen starvation. Rkr1 ubiquitinates Rpl25 within the large (60S) ribosomal subunit. The Ubp3-Bre5 complex, together with its binding partners Cdc48 and Doa1/Ufd3, is required for selective de-ubiquitination of the 60S ribosomal leading to its subsequent turnover by ribophagy. The small (40S) ribosomal subunit is also recruited to the phagophore through a distinct, unknown mechanism. Potential receptors at the phagophore responsible for ribosome recognition remain unknown (see text for details).
Figure 4.
Figure 4.
Post-transcriptional regulation of autophagy mRNAs. Multiple RNA-binding proteins (RBPs) and noncoding RNAs (ncRNAs) are involved in post-translational regulation of autophagy-relevant mRNAs. (A) Downregulation of a number of Atg mRNAs is mediated via Dhh1/DDX6 and Dcp2/DCP2, causing subsequent 5′–3′ exonucleolytic decay both in yeast and humans. (B) In Drosophila the orb protein recognizes cytoplasmic polyadenylation elements (CPEs) in RNA and recruits the major cellular deadenylase complex CCR4-NOT to dampen Atg mRNA levels. (C) Proteins from the ELAV/Hu family, ELAVL4/HuD and ELAVL1/HuR, can upregulate SQSMT1 and ATG5 mRNAs. Their recruitment is mediated by AU-rich elements (ARE) in RNAs. (D) Stabilization of the Rptor mRNA via binding to TARDBP can lead to increased levels of RPTOR protein. (E) microRNAs (miRNAs) are well studied activators of RNA-induced silencing complex (RISC)-mediated mRNA silencing and are involved in the regulation of multiple autophagy-relevant mRNAs. (F) Long non-coding RNAs (lncRNAs) can act as molecular sponges by antagonizing miRNAs and thereby stabilizing mRNA targets of the miRNA (left). lncRNAs can also bind directly to proteins. The lncRNA NBR2 binds to and activates AMPK (right). Up- or downregulated mRNAs are indicated in green or red, respectively (see text for details).

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