title: A comparative proteome analysis links tyrosine kinase 2 (Tyk2) to the regulation of cellular glucose and lipid metabolism in response to poly(I:C).
abstract: Tyrosine kinase 2 (Tyk2) is an integral part of the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway which relays intracellular signals of various cytokines. Tyk2 crucially contributes to host defense mechanisms against microbial pathogens and to tumor surveillance but also facilitates immune pathologies. Here we investigated the impact of Tyk2 on the macrophage proteome using the synthetic double-stranded RNA analog polyinosinic acid-polycytidylic acid (poly(I:C)) as a mimicry of viral infections. By means of 2D-DIGE in connection with PMF obtained by MALDI-MS and sequence tag determination by MS/MS we unambiguously identified eighteen protein spots corresponding to sixteen distinct proteins that are regulated by poly(I:C) and differentially expressed between wildtype (WT) and Tyk2-deficient macrophages. The majority of these proteins are functionally assigned to cellular immune responses and to metabolism. We show for selected metabolic enzymes, i.e. triosephosphate isomerase (TIM), ATP-citrate synthase (ACLY) and long-chain-fatty-acid-CoA ligase 4 (ACSL4), that Tyk2 affects protein expression transcriptionally and post-transcriptionally. We furthermore confirm the involvement of Tyk2 in the regulation of lipid and carbohydrate metabolism at the level of metabolites. Taken together, our results provide new evidence for important functions of Tyk2 at the molecular interface between innate immunity and cellular metabolism.
authors.affiliation: Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Vienna, Austria.
authors.forename: Tom
authors.initials: T
authors.lastname: Grunert
authors.forename: Nicole R
authors.initials: NR
authors.lastname: Leitner
authors.forename: Martina
authors.initials: M
authors.lastname: Marchetti-Deschmann
authors.forename: Ingrid
authors.initials: I
authors.lastname: Miller
authors.forename: Barbara
authors.initials: B
authors.lastname: Wallner
authors.forename: Marta
authors.initials: M
authors.lastname: Radwan
authors.forename: Claus
authors.initials: C
authors.lastname: Vogl
authors.forename: Thomas
authors.initials: T
authors.lastname: Kolbe
authors.forename: Dagmar
authors.initials: D
authors.lastname: Kratky
authors.forename: Manfred
authors.initials: M
authors.lastname: Gemeiner
authors.forename: Günter
authors.initials: G
authors.lastname: Allmaier
authors.forename: Mathias
authors.initials: M
authors.lastname: Müller
authors.forename: Birgit
authors.initials: B
authors.lastname: Strobl
mesh_terms: D000818:Animals; D050260:Carbohydrate Metabolism / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000235:genetics / Q000276:immunology; D005947:Glucose / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D007113:Immunity, Innate / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D007369:Interferon Inducers / Q000494:pharmacology*; D050356:Lipid Metabolism / Q000187:drug effects* / Q000235:genetics / Q000276:immunology; D008264:Macrophages / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D011070:Poly I-C / Q000494:pharmacology*; D020543:Proteome / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D053634:TYK2 Kinase / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
chemical_list: D007369:Interferon Inducers; D020543:Proteome; D053634:TYK2 Kinase; C499356:Tyk2 protein, mouse; D005947:Glucose; D011070:Poly I-C