Protein Inhibitor of Activated STAT (PIAS) Negatively Regulates the JAK/STAT Pathway by Inhibiting STAT Phosphorylation and Translocation

Abstract

Protein inhibitor of activated STAT (PIAS) proteins are activation-suppressing proteins for signal transducer and activator of transcription (STAT), which involves gene transcriptional regulation. The inhibitory mechanism of PIAS proteins in the Janus kinase (JAK)/STAT signaling pathway has been well studied in mammals and Drosophila. However, the roles of PIAS in crustaceans are unclear. In the present study, we identified PIAS in kuruma shrimp Marsupenaeus japonicus and found that its relative expression could be induced by Vibrio anguillarum stimulation. To explore the function of PIAS in shrimp infected with V. anguillarum, we performed an RNA interference assay. After knockdown of PIAS expression in shrimp subjected to V. anguillarum infection, bacterial clearance was enhanced and the survival rate increased compared with those in the control shrimp (dsGFP injection). Simultaneously, the expression levels of antimicrobial peptides (AMPs), including anti-lipopolysaccharide factor (ALF) A1, C1, C2, and CruI-1, increased. Further study revealed that knockdown of PIAS also enhanced STAT phosphorylation and translocation. Pulldown assay indicated that PIAS interacts with activated STAT in shrimp. In conclusion, PIAS negatively regulates JAK/STAT signaling by inhibiting the phosphorylation and translocation of STAT through the interaction between PIAS and STAT, which leads to the reduction of AMP expression in shrimp. Our results revealed a new mechanism of PIAS-mediated gene regulation of the STAT signal pathway.

JAK-STAT Signaling: A Double-Edged Sword of Immune Regulation and Cancer Progression

“…The rapid induction of SOCS upon STAT activation dictates the duration and intensity of a JAK-STAT response, as do the interactions between members of the PIAS (protein inhibitor of activated STAT) family and STAT dimers upon cytokine induction of JAK-STAT pathways. PIAS proteins, which possess E3 SUMO ligase activity, chiefly prevent STAT-mediated gene induction by physically blocking the DNA binding activity of translocated STATs in the nucleus [135], with the exception of PIASy and PIASx, which inhibit STAT signal transduction by recruitment of co-repressors, such as histone deacetylases (HDACs) [136]. PIAS1 is a potent inhibitor of STAT1-dependent type I and II IFN signaling, and it has been found to be upregulated in several malignancies, including metastatic prostate cancer [137,138].…”

Redox Regulation of STAT1 and STAT3 Signaling

“…The specific PIAS-STAT interaction is cytokine-dependent and, within the PIAS family, the different proteins act through different mechanisms. PIAS1 and PIAS3 were identified as interaction partners for STAT1 and STAT3, respectively and have been shown to function also through a SUMO E3 ligase-like mechanism promoting the conjugation of transcriptional factors with the Small Ubiquitin-like Modifier (SUMO) [ 35 ]. Otherwise PIASY is a transcriptional corepressor of STAT1 and its LXXLL coregulator signature motif, located at the NH2 terminus, is involved in the modulation of STAT-mediated gene expression [ 36 ].…”

JAK/STAT signaling in hepatocellular carcinoma

“…Homeostatic regulation of JAK/STAT signaling is mediated by negative regulators that work at multiple levels of the pathway. These include phosphatases that remove phosphate groups from JAKs and STATs, some SOCS proteins that can competitively bind to receptor binding sites of STATs and can target JAK/STATs for proteasomal degradation, as well as protein inhibitors of activated STAT (PIAS), which prevents DNA binding and nuclear translocation of STATs [24,29]. As transcription of SOCS genes are regulated by STATs, this negative feedback loop provides an additional level of control over the pathway and ensures that activation of JAK/STAT signaling is transient.…”