Novel non-canonical role of STAT1 in Natural Killer cell cytotoxicity. (1st September 2016)

• Record Type: Journal Article
• Authors: Putz, Eva Maria; Majoros, Andrea; Gotthardt, Dagmar; Prchal-Murphy, Michaela; Zebedin-Brandl, Eva Maria; Fux, Daniela Alexandra; Schlattl, Andreas; Schreiber, Robert D.; Carotta, Sebastian; Müller, Mathias; Gerner, Christopher; Decker, Thomas; Sexl, Veronika
• Is Part Of: Oncoimmunology. Volume 5:Number 9(2016)
• Publication Date: 2016-09-01
• Subjects: Interactome; NK cell -- STAT1 -- tumor surveillance -- vesicle; Tumors -- Immunological aspects -- Periodicals; Neoplasms -- therapy -- Periodicals; Immunotherapy -- Periodicals; 616.994
• DOI: 10.1080/2162402X.2016.1186314
• Languages: English
• ISSNs: 2162-402X

Abstract

ABSTRACT: STAT1 is an important regulator of NK cell maturation and cytotoxicity. Although the consequences of Stat1 -deficiency have been described in detail the underlying molecular functions of STAT1 in NK cells are only partially understood. Here, we describe a novel non-canonical role of STAT1 that was unmasked in NK cells expressing a Stat1-Y701F mutant. This mutation prevents JAK-dependent phosphorylation, subsequent nuclear translocation and cytokine-induced transcriptional activity as verified by RNA-seq analysis. As expected Stat1-Y701F mice displayed impaired NK cell maturation comparable to Stat1 −/− animals. In contrast Stat1-Y701F NK cells exerted a significantly enhanced cytotoxicity in vitro and in vivo compared to Stat1 −/− NK cells in the absence of detectable transcriptional activity. We thus investigated the STAT1 interactome using primary NK cells derived from Stat1 ind mice that inducibly express a FLAG-tagged STAT1. Mass spectrometry revealed that STAT1 directly binds proteins involved in cell junction formation and proteins associated to membrane or membrane-bound vesicles. In line, immunofluorescence studies uncovered the recruitment of STAT1 to the target-cell interphase during NK cell killing. This led us to propose a novel function for STAT1 at the immunological synapse in NK cells regulating tumor surveillance and cytotoxicity.