| Structural highlights
Function
SID1_CAEEL Plays a role in RNA-mediated gene silencing by acting cell-autonomously as a channel for the transport of double-stranded RNA (dsRNA) between cells. Mediates the spread of dsRNA and subsequent silencing of genes in cells distant from the site of dsRNA introduction. Selective for dsRNA. Preferentially binds long dsRNA, from 50 base pairs up to 700. Short 20 base-pair long molecules are not bound. May also bind dsDNA, but with lower affinity. Binding may be sequence-independent (PubMed:26067272). Required for avoidance behavior induced by small RNAs derived from pathogenic bacteria such as P.aeruginosa (PubMed:32908307).[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13]
Publication Abstract from PubMed
RNA uptake by cells is critical for RNA-mediated gene interference (RNAi) and RNA-based therapeutics. In Caenorhabditis elegans, RNAi is systemic as a result of SID-1-mediated double-stranded RNA (dsRNA) across cells. Despite the functional importance, the underlying mechanisms of dsRNA internalization by SID-1 remain elusive. Here we describe cryogenic electron microscopy structures of SID-1, SID-1-dsRNA complex and human SID-1 homologs SIDT1 and SIDT2, elucidating the structural basis of dsRNA recognition and import by SID-1. The homodimeric SID-1 homologs share conserved architecture, but only SID-1 possesses the molecular determinants within its extracellular domains for distinguishing dsRNA from single-stranded RNA and DNA. We show that the removal of the long intracellular loop between transmembrane helix 1 and 2 attenuates dsRNA uptake and systemic RNAi in vivo, suggesting a possible endocytic mechanism of SID-1-mediated dsRNA internalization. Our study provides mechanistic insights into dsRNA internalization by SID-1, which may facilitate the development of dsRNA applications based on SID-1.
Structural insights into double-stranded RNA recognition and transport by SID-1.,Zhang J, Zhan C, Fan J, Wu D, Zhang R, Wu D, Chen X, Lu Y, Li M, Lin M, Gong J, Jiang D Nat Struct Mol Biol. 2024 Jul;31(7):1095-1104. doi: 10.1038/s41594-024-01276-9. , Epub 2024 Apr 25. PMID:38664565[14]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Winston WM, Molodowitch C, Hunter CP. Systemic RNAi in C. elegans requires the putative transmembrane protein SID-1. Science. 2002 Mar 29;295(5564):2456-9. PMID:11834782 doi:10.1126/science.1068836
- ↑ Feinberg EH, Hunter CP. Transport of dsRNA into cells by the transmembrane protein SID-1. Science. 2003 Sep 12;301(5639):1545-7. PMID:12970568 doi:10.1126/science.1087117
- ↑ Tijsterman M, May RC, Simmer F, Okihara KL, Plasterk RH. Genes required for systemic RNA interference in Caenorhabditis elegans. Curr Biol. 2004 Jan 20;14(2):111-6. PMID:14738731 doi:10.1016/j.cub.2003.12.029
- ↑ Hunter CP, Winston WM, Molodowitch C, Feinberg EH, Shih J, Sutherlin M, Wright AJ, Fitzgerald MC. Systemic RNAi in Caenorhabditis elegans. Cold Spring Harb Symp Quant Biol. 2006;71:95-100. PMID:17381285 doi:10.1101/sqb.2006.71.060
- ↑ Shih JD, Fitzgerald MC, Sutherlin M, Hunter CP. The SID-1 double-stranded RNA transporter is not selective for dsRNA length. RNA. 2009 Mar;15(3):384-90. PMID:19155320 doi:10.1261/rna.1286409
- ↑ Jose AM, Smith JJ, Hunter CP. Export of RNA silencing from C. elegans tissues does not require the RNA channel SID-1. Proc Natl Acad Sci U S A. 2009 Feb 17;106(7):2283-8. PMID:19168628 doi:10.1073/pnas.0809760106
- ↑ Calixto A, Chelur D, Topalidou I, Chen X, Chalfie M. Enhanced neuronal RNAi in C. elegans using SID-1. Nat Methods. 2010 Jul;7(7):554-9. PMID:20512143 doi:10.1038/nmeth.1463
- ↑ Shih JD, Hunter CP. SID-1 is a dsRNA-selective dsRNA-gated channel. RNA. 2011 Jun;17(6):1057-65. PMID:21474576 doi:10.1261/rna.2596511
- ↑ Kobayashi I, Tsukioka H, Kômoto N, Uchino K, Sezutsu H, Tamura T, Kusakabe T, Tomita S. SID-1 protein of Caenorhabditis elegans mediates uptake of dsRNA into Bombyx cells. Insect Biochem Mol Biol. 2012 Feb;42(2):148-54. PMID:22178129 doi:10.1016/j.ibmb.2011.11.007
- ↑ Mon H, Kobayashi I, Ohkubo S, Tomita S, Lee J, Sezutsu H, Tamura T, Kusakabe T. Effective RNA interference in cultured silkworm cells mediated by overexpression of Caenorhabditis elegans SID-1. RNA Biol. 2012 Jan;9(1):40-6. PMID:22293577 doi:10.4161/rna.9.1.18084
- ↑ McEwan DL, Weisman AS, Hunter CP. Uptake of extracellular double-stranded RNA by SID-2. Mol Cell. 2012 Sep 14;47(5):746-54. PMID:22902558 doi:10.1016/j.molcel.2012.07.014
- ↑ Li W, Koutmou KS, Leahy DJ, Li M. Systemic RNA Interference Deficiency-1 (SID-1) Extracellular Domain Selectively Binds Long Double-stranded RNA and Is Required for RNA Transport by SID-1. J Biol Chem. 2015 Jul 31;290(31):18904-13. PMID:26067272 doi:10.1074/jbc.M115.658864
- ↑ Kaletsky R, Moore RS, Vrla GD, Parsons LR, Gitai Z, Murphy CT. C. elegans interprets bacterial non-coding RNAs to learn pathogenic avoidance. Nature. 2020 Oct;586(7829):445-451. PMID:32908307 doi:10.1038/s41586-020-2699-5
- ↑ Zhang J, Zhan C, Fan J, Wu D, Zhang R, Wu D, Chen X, Lu Y, Li M, Lin M, Gong J, Jiang D. Structural insights into double-stranded RNA recognition and transport by SID-1. Nat Struct Mol Biol. 2024 Jul;31(7):1095-1104. PMID:38664565 doi:10.1038/s41594-024-01276-9
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