title: Modified siRNA effectively silence inducible immunoproteasome subunits in NSO cells.
abstract: The pathogenesis of autoimmune and neurodegenerative diseases involves overexpression of inducible subunits of the immunoproteasome. However, the clinical application of inhibitors to inducible subunits of the immunoproteasome has been limited due to systemic toxicity. Here, we designed siRNAs that efficiently silence LMP2, LMP7 and MECL-1 gene expression. Inducible subunits of the immunoproteasome are complex siRNA targets because they have a long half-life; therefore, we introduced 2'-O-methyl modifications into nuclease-sensitive sites. This led to 90-95% silencing efficiency and prolonged silencing, eliminating the need for multiple transfections. Furthermore, we showed that in the absence of transfection reagent, siRNAs with lipophilic residues were able to penetrate cells more effectively and decrease the expression of inducible immunoproteasome subunits by 35% after 5 days. These results show that siRNA targeted to inducible immunoproteasome subunits have great potential for the development of novel therapeutics for autoimmune and neurodegenerative diseases.
authors.affiliation: Institute of Chemical Biology and Fundamental Medicine SB RAS, 8, Lavrentiev Avenue, Novosibirsk, 630090, Russia.
authors.forename: Olga V
authors.initials: OV
authors.lastname: Gvozdeva
authors.affiliation: M.M. Shemyakin and Yu.A. Ovchinnikov Institute of Bioorganic Chemistry RAS, 16/10, Miklukho-Maklaya str., Moscow, 117997, Russia; Institute of Fundamental Medicine and Biology, Kazan Federal University, 18 Kremlyovskaya str., Kazan, Tatarstan, 420008 Russia.
authors.forename: Alexey A
authors.initials: AA
authors.lastname: Belogurov
authors.affiliation: M.M. Shemyakin and Yu.A. Ovchinnikov Institute of Bioorganic Chemistry RAS, 16/10, Miklukho-Maklaya str., Moscow, 117997, Russia.
authors.forename: Ekaterina S
authors.initials: ES
authors.lastname: Kuzina
authors.affiliation: M.M. Shemyakin and Yu.A. Ovchinnikov Institute of Bioorganic Chemistry RAS, 16/10, Miklukho-Maklaya str., Moscow, 117997, Russia; Institute of Fundamental Medicine and Biology, Kazan Federal University, 18 Kremlyovskaya str., Kazan, Tatarstan, 420008 Russia.
authors.forename: Alexander G
authors.initials: AG
authors.lastname: Gabibov
authors.affiliation: Institute of Chemical Biology and Fundamental Medicine SB RAS, 8, Lavrentiev Avenue, Novosibirsk, 630090, Russia.
authors.forename: Mariya I
authors.initials: MI
authors.lastname: Meschaninova
authors.affiliation: Institute of Chemical Biology and Fundamental Medicine SB RAS, 8, Lavrentiev Avenue, Novosibirsk, 630090, Russia.
authors.forename: Alya G
authors.initials: AG
authors.lastname: Ven'yaminova
authors.affiliation: Institute of Chemical Biology and Fundamental Medicine SB RAS, 8, Lavrentiev Avenue, Novosibirsk, 630090, Russia.
authors.forename: Marina A
authors.initials: MA
authors.lastname: Zenkova
authors.affiliation: Institute of Chemical Biology and Fundamental Medicine SB RAS, 8, Lavrentiev Avenue, Novosibirsk, 630090, Russia.
authors.forename: Valentin V
authors.initials: VV
authors.lastname: Vlassov
authors.affiliation: Institute of Chemical Biology and Fundamental Medicine SB RAS, 8, Lavrentiev Avenue, Novosibirsk, 630090, Russia. Electronic address: elena_ch@niboch.nsc.ru.
authors.forename: Elena L
authors.initials: EL
authors.lastname: Chernolovskaya
mesh_terms: D002460:Cell Line; D003546:Cysteine Endopeptidases / Q000096:biosynthesis / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D020868:Gene Silencing / Q000187:drug effects*; D006801:Humans; D046988:Proteasome Endopeptidase Complex / Q000096:biosynthesis / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics / Q000494:pharmacology
chemical_list: D034741:RNA, Small Interfering; C071313:LMP-2 protein; D003546:Cysteine Endopeptidases; C077436:LMP7 protein; C098948:PSMB10 protein, human; D046988:Proteasome Endopeptidase Complex
keywords: Chemical modifications; Immunoproteasome; NSO cells; siRNA