title: Two independent mechanisms promote expression of an N-terminal truncated USP18 isoform with higher DeISGylation activity in the nucleus.
abstract: Expression of the ISG15 specific protease USP18 is highly induced by type I interferons. The two main functions of USP18, i.e. its enzymatic activity and down-regulation of type I interferon signaling, are well characterized. However, to date all functional studies focused on full-length USP18. Here, we report that translation of human USP18 is initiated by a rare start codon (CUG). Usage of this non-canonical initiation site with its weak translation initiation efficiency promotes expression of an N-terminal truncated isoform (USP18-sf). In addition, an internal ribosome entry site (IRES) located in the 5'-coding region of USP18 also contributes to translation of USP18-sf. Functionally, both isoforms exhibit enzymatic activity and interfere with type I interferon signaling. However, USP18-sf shows different subcellular distribution compared with the full-length protein and enhanced deISGylation activity in the nucleus. Taken together, we report the existence of an N-terminal truncated isoform of USP18, whose expression is controlled on translational level by two independent mechanisms providing translational flexibility as well as cell type-specific resistance to inhibition of cap-dependent translation.
authors.affiliation: Moores Cancer Center, University of California San Diego, La Jolla, California 92093, USA.
authors.forename: Christoph
authors.initials: C
authors.lastname: Burkart
authors.forename: Jun-Bao
authors.initials: JB
authors.lastname: Fan
authors.forename: Dong-Er
authors.initials: DE
authors.lastname: Zhang
mesh_terms: D002467:Cell Nucleus / Q000201:enzymology* / Q000235:genetics; D018387:Codon, Initiator / Q000235:genetics / Q000378:metabolism*; D010450:Endopeptidases / Q000096:biosynthesis* / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D007527:Isoenzymes / Q000096:biosynthesis / Q000235:genetics; D019169:Jurkat Cells; D010442:Peptide Chain Initiation, Translational / Q000502:physiology*; D043222:Ubiquitin Thiolesterase
chemical_list: D018387:Codon, Initiator; D007527:Isoenzymes; D010450:Endopeptidases; C485560:USP18 protein, human; D043222:Ubiquitin Thiolesterase