SIDT2 RNA Transporter Promotes Lung and Gastrointestinal Tumor Development

Abstract

SummaryRNautophagy is a newly described type of selective autophagy whereby cellular RNAs are transported into lysosomes for degradation. This process involves the transmembrane protein SIDT2, which transports double-stranded RNA (dsRNA) across the endolysosomal membrane. We previously demonstrated that SIDT2 is a transcriptional target of p53, but its role in tumorigenesis, if any, is unclear. Unexpectedly, we show here that Sidt2−/− mice with concurrent oncogenic KrasG12D activation develop significantly fewer tumors than littermate controls in a mouse model of lung adenocarcinoma. Consistent with this observation, loss of SIDT2 also leads to enhanced survival and delayed tumor development in an Apcmin/+ mouse model of intestinal cancer. Within the intestine, Apcmin/+;Sidt2−/− mice display accumulation of dsRNA in association with increased phosphorylation of eIF2α and JNK as well as elevated rates of apoptosis. Taken together, our data demonstrate a role for SIDT2, and by extension RNautophagy, in promoting tumor development.

Identification of Key Deregulated RNA-Binding Proteins in Pancreatic Cancer by Meta-Analysis and Prediction of Their Role as Modulators of Oncogenesis

“…Lastly, in order to further verify the expression status of altered RBPs in pancreatic cancer cell lines and tissue samples, we explored the published literature and used The Protein Atlas data. There were multiple studies where actually the expression of these specific RBPs was estimated in several pancreatic cancer cell lines or patient tissues using qPCR and/or Western blotting or immunohistochemical analysis; convincingly supporting our results ( Supplementary Table S8 ) ( Fernández-Salas et al, 2000 ; Kong et al, 2010 ; Bhatti et al, 2011 ; Taniuchi et al, 2014a ; Cai et al, 2015 ; Taniuchi et al, 2015 ; Schultz et al, 2017 ; Tang et al, 2017 ; Yu et al, 2017 ; Nguyen et al, 2019 ; Cui et al, 2020 ; Konishi et al, 2021 ). Immunohistochemistry results for IGF2BP3, PAIP2B, and SIDT2 have already been shown in Figure 2 , and we additionally present the results for the rest of the five RBPs in pancreatic cancer tissues as shown in Supplementary Figure S4 , which strongly validate their expression in patient samples signifying their importance in the disease.…”

Adipose tissue macrophage-derived exosomal miR-210-5p in modulating insulin sensitivity in rats born small for gestational age with catch-up growth

“…We identified SIDT2 as a potential target of miR-210-5p using a bioinformatics approach. SIDT2 is a lysosomal integral membrane protein that is widely expressed in mammalian tissue (27,28). Previous studies have revealed that SIDT2 mediated an array of cellular biological responses, including autophagy, lipid metabolism, inflammation, and insulin sensitivity (29)(30)(31).…”

Extracellular mRNA transported to the nucleus exerts translation-independent function

“…Furthermore, the specific interaction of IL1β- mRNA was mediated by ZC3H12D protein, which recognizes its 3′ - UTR; this is not surprising, as many mRNA-binding proteins bind to secondary structures, including stem loops and short consensus sequences, such as AREs, which are situated in the 3′ - UTR of many transcripts in the cytoplasm 32 . Also, extracellular double-stranded RNA is nonspecifically recruited into the cytoplasm by the S1D family, resulting in the usage of cellular RNA interference silencing 52 – 54 . So far, several types of RNA uptake inside cells have been reported, and some of them are utilized in gene therapies 55 .…”