Reexamination of the role of ubiquitin-like modifier ISG15 in the phenotype of UBP43-deficient mice.
UBP43/USP18 was described as a specific protease that removes conjugated ubiquitin-like modifier ISG15 from target proteins. The severe phenotype of UBP43(-/-) mice characterized by premature death, brain cell injury, and deregulated STAT1 signaling was ascribed to an enhanced conjugation of ISG15. In contrast, no phenotypic changes were detected in ISG15(-/-) mice. To verify the role of ISG15 in the phenotype of UBP43(-/-) mice, we employed mice deficient for both ISG15 and UBP43. Here, we show that the phenotype of UBP43(-/-) mice was not rescued by the absence of ISG15, as evident from unchanged mortality, neurological symptoms, and occurrence of hydrocephalus. Also, the reported hypersensitivity of UBP43(-/-) mice to an interferon inducer, poly(I . C), was ISG15 independent. Furthermore, no evidence for a role of ISG15 in the modulation of STAT1 signaling or in the resistance against lymphocytic choriomeningitis virus and vesicular stomatitis virus was found. Presented results clearly demonstrate that the phenotypic alterations of UBP43(-/-) mice are not caused by the lack of ISG15 deconjugation and must be due to another, non-ISG15-mediated molecular mechanism.
Knobeloch
Klaus-Peter
KP
Abteilung für Molekulare Genetik, Institut für Molekulare Pharmakologie, and Charité Universitätsmedizin, Berlin, Germany.
Utermöhlen
Olaf
O
Kisser
Agnes
A
Prinz
Marco
M
Horak
Ivan
I
D000818:Animals; D001117:Arenaviridae Infections / Q000276:immunology; D001927:Brain Diseases / Q000235:genetics / Q000473:pathology; D016207:Cytokines / Q000172:deficiency / Q000235:genetics* / Q000502:physiology*; D004342:Drug Hypersensitivity / Q000235:genetics; D010450:Endopeptidases / Q000172:deficiency / Q000235:genetics*; D015870:Gene Expression / Q000187:drug effects; D006849:Hydrocephalus / Q000235:genetics / Q000473:pathology; D007113:Immunity, Innate / Q000235:genetics; D007372:Interferons / Q000494:pharmacology; D008217:Lymphocytic choriomeningitis virus; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D010641:Phenotype; D011070:Poly I-C / Q000633:toxicity; D018353:Rhabdoviridae Infections / Q000276:immunology; D050794:STAT1 Transcription Factor / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism; D043222:Ubiquitin Thiolesterase; D014452:Ubiquitins / Q000172:deficiency / Q000235:genetics / Q000502:physiology
D016207:Cytokines; C489550:G1p2 protein, mouse; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D025801:Ubiquitin; D014452:Ubiquitins; D007372:Interferons; D010450:Endopeptidases; C118306:Usp18 protein, mouse; D043222:Ubiquitin Thiolesterase; D011070:Poly I-C