Regulation of antiviral immunity and autoimmune inflammation by the deubiquitinating enzyme USP15
Final Report Abstract
USP15 is a deubiquitinating enzyme previously reported to be critical for TypeI IFN induction within the context of neuroinflammation, where lack of USP15 protects against cerebral malaria and experimental autoimmune encephalomyelitis (EAE) in mice. This and the observation that USP15 is inducible by various pathogen associated danger signals suggested a generalized role of USP15 in the IFN response. However, infection of newly generated USP15 KO mice with VSV, a typical IFN I sensitive virus, did not provide evidence of altered survival. Likewise, we were unable to validate altered TRIM25 ubiquitination reported upon loss of USP15. Likewise, experimental mesial temporal lobe epilepsy was unaffected by constitutive or conditionally induced USP15 deficiency. Of note, reduced bodyweight and body size was observed in USP15 KO mice, suggesting metabolic alterations. Fat cell differentiation was unaltered and accordingly Adipo-Cre mediated deletion of USP15 in fat cells did not affect body weight. Despite reduced body size, bone development was also unaffected by the loss of USP15. Remarkably, we observed that USP15-/- mice displayed increased oral glucose tolerance and insulin sensitivity, altered IGFBP1 gene expression and PKB activation profiles. In summary, we found that USP15 plays an important role in insulin/IGF controlled glucose homeostasis and growth control. Unbiased RNA profiling of USP15 WT and KO liver tissue upon 4h starvation uncovered deregulated expression of several genes associated with metabolism. To pinpoint the molecular mechanisms, whole proteome analysis, unbiased comparative analysis of the ubiquitinome by diGly analysis and interactome analysis was performed. Results are currently more closely investigated to decipher the mechanisms underlying the role of USP15 in metabolism. A marked deregulation of MACROD1 protein levels was identified. Despite this protein was associated with mitochondrial homeostasis, morphological and EM evaluation of muscles of WT and USP15 KO mice did not detect any gross alterations in overall muscle or mitochondrial morphology. However, Macrod1 may also play a role in RNA processing, a function that appears to be prominent with respect to the identified highly significant spliceosomal interactions of USP15.
Publications
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Untersuchung von gendefizienten Mäusen und molekulare Analysen zur Funktion und Regulation der Ubiquitin Isopeptidase USP15
Solveig Mosthaf
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Downregulation of Ubiquitin-Specific Protease 15 (USP15) Does Not Provide Therapeutic Benefit in Experimental Mesial Temporal Lobe Epilepsy. Molecular Neurobiology, 61(4), 2367-2389.
Häussler, Ute; Neres, João; Vandenplas, Catherine; Eykens, Caroline; Kadiu, Irena; Schramm, Carolin; Fleurance, Renaud; Stanley, Phil; Godard, Patrice; de Mot, Laurane; van Eyll, Jonathan; Knobeloch, Klaus-Peter; Haas, Carola A. & Dedeurwaerdere, Stefanie
