Regulatory effects of SKAR in interferon α signaling and its role in the generation of type I IFN responses

Barbara Kroczynska, Swarna Mehrotra, Beata Majchrzak-Kita, Ahmet Dirim Arslan, Jessica K. Altman, Brady L. Stein, Brandon McMahon, Piotr Kozlowski, Philipp J. Kahle, Elizabeth A. Eklund, Eleanor N. Fish, Leonidas C. Platanias*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

We provide evidence that S6 kinase 1 (S6K1) Aly/REF-like target (SKAR) is engaged in IFN-α signaling and plays a key role in the generation of IFN responses. Our data demonstrate that IFN-α induces phosphorylation of SKAR, which is mediated by either the p90 ribosomal protein S6 kinase (RSK) or p70 S6 kinase (S6K1), in a cell type-specific manner. This type I IFN-inducible phosphorylation of SKAR results in enhanced interaction with the eukaryotic initiation factor (eIF)4G and recruitment of activated RSK1 to 5′ cap mRNA. Our studies also establish that SKAR is present in cap-binding CBP80 immune complexes and that this interaction is mediated by eIF4G. We demonstrate that inducible protein expression of key IFN-α-regulated protein products such as ISG15 and p21WAF1/CIP1 requires SKAR activity. Importantly, our studies define a requirement for SKAR in the generation of IFN-α-dependent inhibitory effects on malignant hematopoietic progenitors from patients with chronic myeloid leukemia or myeloproliferative neoplasms. Taken altogether, these findings establish critical and essential roles for SKAR in the regulation of mRNA translation of IFN-sensitive genes and induction of IFN-α biological responses.

Original languageEnglish (US)
Pages (from-to)11377-11382
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number31
DOIs
StatePublished - Aug 5 2014

ASJC Scopus subject areas

  • General

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