Lysosomal systemic RNA interference defective protein-2, (systemic RNAi-defective (SID)) SidT2 of 832 aas and 12 TMSs in a 1 (N-terminal) + 1 (at residue 300) + 10 TMS arrangement. It increases the uptake of exogenous dsRNA and DNA (Aizawa et al. 2016).  RNA and DNA are directly taken up by lysosomes in an ATP-dependent manner and degraded. SIDT2 has been reported to mediate RNA translocation during RNA autophagy and DNA translocation during DNA autophagy. Knockdown of Sidt2 inhibited, up to ~50%, total RNA degradation at the cellular level, independently of macroautophagy (Aizawa et al. 2016).  RNA autophagy plays a role in constitutive cellular RNA degradation. SIDT2 also takes up single stranded oligonucleotides into cells (Takahashi et al. 2017). Contu et al. 2017 showed that three cytosolic YXXPhi motifs in SIDT2 are required for the lysosomal localization of SIDT2, and that SIDT2 interacts with adaptor protein complexes AP-1 and AP-2.  On the other hand, Méndez-Acevedo et al. 2017 reported that this protein and SIDT1 transport cholesterol and not RNA. SIDT2 and RNautophagy promote tumor development (Nguyen et al. 2019). The cytosolic domain of SIDT2 carries an arginine-rich motif that binds to RNA/DNA and is important for the direct transport of nucleic acids into lysosomes (Hase et al. 2020). SIDT2 influences the three inflammatory signal pathways, eventually leading to damage of glomerular mesangial cells in mice (Sun et al. 2020). The variant rs1784042 of the SIDT2 gene is associated with the metabolic syndrome through Low HDL-c levels (León-Reyes et al. 2020). SidT2 enhances glucose uptake in peripheral tissues upon insulin stimulation (Xiong et al. 2020). The LIFR-AS1/miR-31-5p/SIDT2 axis modulated the development of papillary thyroid carcinoma (PTC) (Yi et al. 2021).  The cryo-EM structures of human SIDT2 forms a tightly packed dimer with extensive interactions mediated by two previously uncharacterized extracellular/luminal beta-strand-rich domains and the unique transmembrane domain (TMD) (Qian et al. 2023). The TMD of each SIDT2 protomer contains eleven TMSs), and no discernible nucleic acid conduction pathway within the TMD, suggesting that it may act as a transporter. TM3-6 and TM9-11 form a large cavity with a putative catalytic zinc atom coordinated by three conserved histidine residues and one aspartate residue lying approximately 6 Å from the extracellular/luminal surface of the membrane. SIDT2 can hydrolyze C18 ceramide into sphingosine and fatty acid with a slow rate (Qian et al. 2023). SIDT2 inhibits phosphorothioate Aantisense oligonucleotide activity by regulating cellular localization of lysosomes (Zhao et al. 2023).  SIDT2 is a player in cholesterol and lipoprotein metabolism in humans (León-Mimila et al. 2021).  SIDT2 increases knockdown activity of gapmer antisense oligonucleotides (Kusumoto et al. 2025).