SIDT2 Membrane Protein Introduction

Introduction of SIDT2

SID1 transmembrane family member 2 (SIDT2) is a protein that widely exists in human. Its molecular weight detected in multiple tissues of mouse and rat is approximately 95 kDa. In rats, SIDT2 is highly expressed in the liver, brain, and kidney. SIDT2 is a highly glycosylated lysosomal integral membrane protein that shows tissue-specific expression. It has been also reported that SIDT2 is associated with the host's antiviral defense mechanism. SIDT2 may also play a critical role in the regulation of insulin secretory granule secretion by NAADP-mediated releasing of calcium from insulin secretory granules.

Function of SIDT2 Membrane Protein

SIDT2 can mediate the translocation of RNA and DNA across the lysosomal membrane during RNA and DNA autophagy (RDA), in which RNA or DNA can be directly imported into lysosomes with ATP-dependent manner. It involves in the uptake of single-stranded oligonucleotides in living cells, a process called gymnosis. It also regulates DNA/RNA binding. In vitro, SIDT2 influences the uptake of linear DNA more efficiently than its effect on circular DNA. However, it exhibits similar efficacy toward RNA and DNA uptake. It can also bind to long double-stranded RNA (dsRNA) (500 - 700 base pairs), but not dsRNA shorter than 100 bp. Moreover, it takes part in many biological processes, such as type B pancreatic cell development, response to glucose and regulation of insulin secretion involved in the cellular response to a glucose stimulus.

Fig.1 The endo-lysosomal protein SIDT2 transports double-stranded RNA into the cytoplasm in RLR signaling. (Nguyen, 2017)

Application of SIDT2 Membrane Protein in Literature

1. Nguyen T.A., et al. SIDT2 Transports Extracellular dsRNA into the Cytoplasm for Innate Immune Recognition. Immunity. 2017, 47(3): 498-509. PubMed ID: 28916264
   
   

   This article shows that the mammalian SID-1 ortholog, SIDT2, is required for transporting internalized extracellular dsRNA from endocytic compartments into the cytoplasm for immune activation. Being exposed to extracellular dsRNA, encephalomyocarditis virus (EMCV), and herpes simplex virus 1 (HSV-1), mice lack SIDT2 will show impaired production of antiviral cytokines and EMCV and HSV-1-reduced survival.

2. Jialin G., et al. SID1 transmembrane family, member 2 (Sidt2): a novel lysosomal membrane protein. Biochem Biophys Res Commun. 2010, 402(4): 588-94. PubMed ID: 20965152
   
   

   This article demonstrates that Sidt2 is a lysosomal integral membrane protein with tissue-specific expression. After digested with PNGase F, the apparent molecular mass of Sidt2 decreases to the predicted value of 95kDa. In rats, Sidt2 is highly expressed in the liver, brain, and kidney, whereas no or little expression is found in the skeletal muscles, heart, and other tissues.

3. Ren R., et al. Cloning, characterization, and biological function analysis of the SidT2 gene from Siniperca chuatsi. Dev Comp Immunol. 2011, 35(6): 692-701. PubMed ID: 21334374
   
   

   The authors identify the ScSidT2 gene from the mandarin fish (Siniperca chuatsi). It contains a 2568-bp open reading frame that encodes an 855-amino-acid protein with an N-terminal signal peptide and ten putative transmembrane domains. Overexpression of ScSidT2 can control virus production and can be significantly promoted by adding virus-specific dsRNA. ScSidT2 is associated with the host's antiviral defense mechanism.

4. Gao J., et al. Impaired glucose tolerance in a mouse model of sidt2 deficiency. PLoS One. 2013, 8(6): e66139. PubMed ID: 23776622
   
   

   In this article, Sidt2 is identified as a novel integral lysosomal membrane protein and plays a critical role in the regulation of mouse insulin secretory granule secretion. Sidt2 knockout mice have a negative change on glucose intolerance and decreased serum insulin level.

5. Aizawa S., et al. Lysosomal putative RNA transporter SIDT2 mediates direct uptake of RNA by lysosomes. Autophagy. 2016, 12(3): 565-78. PubMed ID: 27046251
   
   

   This article suggests that knockdown of Sidt2 inhibits up to 50% of total RNA degradation at the cellular level. It also shows that the impairment is mainly due to inhibition of lysosomal RNA degradation, which strongly suggests that RNA autophagy plays a significant role in constitutive cellular RNA degradation.

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Reference

1. Nguyen, et al. (2017). SIDT2 Transports Extracellular dsRNA into the cytoplasm for Innate Immune Recognition. Immunity. 47: 3.

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