SIDT2 RNA Transporter Promotes Lung and Gastrointestinal Tumor Development

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 Kras(G12D) activation develop significantly fewer tumors than littermate controls in a mousemodel of lung adenocarcinoma. Consistent with this observation, loss of SIDT2 also leads to enhanced survival and delayed tumor development in an Apc(min/+) mouse model of intestinal cancer. Within the intestine, Apc(min/+);Sidt2(-/-) mice display accumulation of dsRNA in association with increased phosphorylation of eIF2 alpha 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.