Lysosomal targeting of SIDT2 via multiple YxxΦ motifs is required for SIDT2 function in the process of RNautophagy

Abstract

RNA degradation is an essential process for maintaining cellular homeostasis. Previously, we discovered a novel RNA degradation system, RNautophagy, during which direct import of RNA into lysosomes in an ATP-dependent manner followed by degradation takes place. The putative nucleic acid transporterSID-1 transmembrane family member 2 (SIDT2) predominantly localizes to lysosomes and mediates the translocation ofRNAinto lysosomes duringRNautophagy. However, little is known about the mechanisms of sorting SIDT2 to lysosomes. Here, we showthat three cytosolic YxxΦ motifs (inwhich x is any amino acid and Φ is an amino acid with a bulky hydrophobic side chain) are required for the lysosomal localization of SIDT2, and that SIDT2 interacts with adaptorproteincomplexes AP-1 and AP-2. We also find that localization to lysosomes by these threemotifs is necessary for SIDT2 function in theprocess of RNautophagy, and that SIDT2 strikingly increases endogenous RNA degradation at the cellular level. To our knowledge, this is the first study to report an endogenous intracellular protein for which overexpression substantially increased intracellular RNA degradation. This study provides new insight into lysosomal targeting of proteins and intracellular RNA degradation, and further confirms the critical function of SIDT2 in RNautophagy. This article has an associated First Person interview with the first author of the paper.