SIDT2 RNA transporter promotes lung and gastrointestinal tumor development

Abstract

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 mouse model of lung adenocarcinoma (LUAD). 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 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.

Structure of the human systemic RNAi defective transmembrane protein 1 (hSIDT1) reveals the conformational flexibility of its lipid binding domain

“…SIDT2 overexpression enhances siRNA transport, while knockdown reduces RNA degradation, and a knockout disturbs the glucose homeostasis [15,24]. Like SIDT1, SIDT2 is also implicated in crucial biological processes such as lysosomal membrane permeability, hepatic lipid homeostasis, apoptosis, and tumor proliferation [14,20,25,26]. Despite SIDTs being a potential target for therapeutics against tumor progression, liver diseases, and Type II diabetes, their exploration as potential drug targets has been impeded by the lack of in vitro transport kinetic studies and high-resolution 3D structures of SIDTs.…”