SIDT2 RNA Transporter Promotes Lung and Gastrointestinal Tumor Development
Tan A. Nguyen,
Kathryn T. Bieging-Rolett,
Tracy L. Putoczki,
Ian P. Wicks,
Laura D. Attardi,
Ken C. Pang
Affiliations
Tan A. Nguyen
The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia
Kathryn T. Bieging-Rolett
Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA, USA; Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA
Tracy L. Putoczki
The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia
Ian P. Wicks
The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia
Laura D. Attardi
Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA, USA; Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA
Ken C. Pang
The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia; Murdoch Children's Research Institute, Parkville, VIC, Australia; Department of Paediatrics, University of Melbourne, Parkville, VIC, Australia; Department of Psychiatry, University of Melbourne, Parkville, VIC, Australia; Corresponding author
Summary: 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. : Biological Sciences; Molecular Biology; Cell Biology; Cancer Subject Areas: Biological Sciences, Molecular Biology, Cell Biology, Cancer
