SIDT2 RNA Transporter Promotes Lung and Gastrointestinal Tumor Development

• Published in: iScience Vol. 20; pp. 14 - 24
• Main Authors: Nguyen, Tan A., Bieging-Rolett, Kathryn T., Putoczki, Tracy L., Wicks, Ian P., Attardi, Laura D., Pang, Ken C.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 25.10.2019; Elsevier
• Subjects: Biological Sciences; Cancer; Cell Biology; Molecular Biology; Biological Sciences; Molecular Biology; Cell Biology; Cancer
• ISSN: 2589-0042; 2589-0042
• DOI: 10.1016/j.isci.2019.09.009

RNautophagy 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. [Display omitted] Loss of the SIDT2 double-stranded RNA (dsRNA) transporter •leads to accumulation of dsRNA in tissues•is associated with increased apoptosis•reduces tumor burden in mouse models of lung adenocarcinoma and intestinal cancer Biological Sciences; Molecular Biology; Cell Biology; Cancer