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Abstract
Four ‘protein inhibitors of activated STAT’ (PIAS) control STAT-dependent and NF-κB-dependent immune signalling in humans. The genome of rainbow trout (Oncorhynchus mykiss) contains eight pias genes, which encode at least 14 different pias transcripts that are differentially expressed in a tissue- and cell-specific manner. Pias1a2 was the most strongly expressed variant among the analysed pias genes in most tissues, while pias4a2 was commonly low or absent. Since the knock-out of Pias factors in salmonid CHSE cells using CRISPR/Cas9 technology failed, three structurally different Pias protein variants were selected for overexpression studies in CHSE-214 cells. All three factors quenched the basal activity of an NF-κB promoter in a dose-dependent fashion, while the activity of an Mx promoter remained unaffected. Nevertheless, all three overexpressed Pias variants from trout strongly reduced the transcript level of the antiviral Stat-dependent mx gene in ifnγ-expressing CHSE-214 cells. Unlike mx, the overexpressed Pias factors modulated the transcript levels of NF-κB-dependent immune genes (mainly il6, il10, ifna3, and stat4) in ifnγ-expressing CHSE-214 cells in different ways. This dissimilar modulation of expression may result from the physical cooperation of the Pias proteins from trout with differential sets of interacting factors bound to distinct nuclear structures, as reflected by the differential nuclear localisation of trout Pias factors. In conclusion, this study provides evidence for the multiplication of pias genes and their sub-functionalisation during salmonid evolution.
Highlights
The signalling through Janus kinases (JAK) and signal transducers and activators of transcription (STAT) [1,2] transfer a wide range of information from the membrane to the nucleus of eukaryotic cells [3,4]
The common adjacency to morf4l1 and uaca indicates that the two pias1 genes on chromosomes 26 and 30 of rainbow trout are ohnologues, pias1a1 and pias1a2
Pias1 on chromosome 2 is flanked by a different set of genes, suggesting that this is a paralogue of pias1a1 and pias1a2 and should be termed pias1b
Summary
The signalling through Janus kinases (JAK) and signal transducers and activators of transcription (STAT) [1,2] transfer a wide range of information from the membrane to the nucleus of eukaryotic cells [3,4]. Upon the stimulus-dependent activation of specific cytokine receptors, the four mammalian JAK proteins (JAK1, JAK2, JAK3, and TYK2) become activated and phosphorylate several other associated proteins, including themselves, other receptor chains, and STAT factors [5] (Table S1). The seven mammalian STAT proteins (STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b, and STAT6) dimerise after phosphorylation and translocate into the nucleus, where they bind to cognate DNA elements. These binding sites are often in close proximity to the response elements of nuclear factor-κB (NF-κB). The NF-κB/Rel family of transcription factors comprises five members (p65/RelA, RelB, c-Rel, and p50/NF-κB1, p52/NF-κB2) in most vertebrates [6]. Only one PIAS protein is present in the lancelet (Branchiostoma sp.) [15]
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