ArticleScientific reports2025
Multispanning membrane protein SIDT2 increases knockdown activity of gapmer antisense oligonucleotides.
Article in Scientific reports, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.
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Who cites it
3 citing papers in PubMed.
- The DNA/RNA autophagy protein SIDT2 as a novel neuropathological hallmark in Huntington disease.Brain pathology (Zurich, Switzerland) · 2026Article
- RNASET2 degrades mRNAs that protect against lipotoxicity.Molecular metabolism · 2026Article
- The lysosomal catabolism of nucleic acids-critical regulators of the innate immune system.Nucleic acids research · 2025Review
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Authors and funding
8 authors.
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Abstract
Recent advances in the clinical development of oligonucleotide therapeutics, such as antisense oligonucleotides (ASOs) and small interfering RNAs, have attracted attention as promising therapeutic modalities for genetic and intractable diseases. These oligonucleotide therapeutics exert their efficacy by binding to target RNAs present within cells; however, the mechanisms underlying their cellular uptake, especially their passage through membranes, remain largely unclear. In the nematode, Caenorhabditis elegans, the multi-pass transmembrane protein, SID-1, is involved in the cellular uptake of double-stranded RNAs. In mammals, SIDT1 and SIDT2 (SID-1 transmembrane family, members 1 and 2, respectively) are homologs of SID-1, yet their functional differences are not fully understood. In this study, we conducted a comparative analysis of the amino acid sequences of mammalian SIDT1 and SIDT2 to identify regions characteristic to each. By inducing SIDT1 or SIDT2 expression in human cell lines, we demonstrated that SIDT2 enhanced the knockdown activity of gapmer ASOs and potentially promoted their endosomal escape into the cytosol. Furthermore, by analyzing chimeric proteins of SIDT2 and SIDT1, we identified a region in SIDT2 that might be crucial for the enhancement of gapmer ASO activity. These findings elucidate the novel role of SIDT2 in the transport mechanism of gapmer ASOs and are expected to contribute to further development of oligonucleotide therapeutics.
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