STAT2 Is a Pervasive Cytokine Regulator due to Its Inhibition of STAT1 in Multiple Signaling Pathways

Autor: Uwe Vinkemeier, Hany M. Elsheikha, Johnathan On Kay Ho, Christin Pelzel, David J. Scott, Maureen Mee, Andreas Begitt
Rok vydání: 2016
Předmět:
0301 basic medicine
Cell signaling
Protein Conformation
Physiology
medicine.medical_treatment
Regulator
Gene Expression
Signal transduction
Biochemistry
Major Histocompatibility Complex
White Blood Cells
0302 clinical medicine
Animal Cells
Immune Physiology
Medicine and Health Sciences
STAT1
Biology (General)
STAT2
Phosphorylation
Post-Translational Modification
STAT3
Innate Immune System
General Neuroscience
STAT signaling
STAT proteins
Cytokine
STAT1 Transcription Factor
Cell Processes
030220 oncology & carcinogenesis
Cytokines
Cellular Types
General Agricultural and Biological Sciences
Dimerization
Protein Binding
Research Article
QH301-705.5
Immune Cells
Immunology
Biology
General Biochemistry
Genetics and Molecular Biology
03 medical and health sciences
Interferon-gamma
medicine
Parasitic Diseases
Animals
Humans
Nuclear Import
Transcription factor
Cell Nucleus
Binding Sites
Blood Cells
General Immunology and Microbiology
Macrophages
Biology and Life Sciences
Proteins
STAT2 Transcription Factor
DNA
Cell Biology
Molecular Development
030104 developmental biology
Immune System
biology.protein
STAT protein
Cancer research
Clinical Immunology
Clinical Medicine
Developmental Biology
Zdroj: PLoS Biology
PLoS Biology, Vol 14, Iss 10, p e2000117 (2016)
ISSN: 1545-7885
1544-9173
Popis: STAT2 is the quintessential transcription factor for type 1 interferons (IFNs), where it functions as a heterodimer with STAT1. However, the human and murine STAT2-deficient phenotypes suggest important additional and currently unidentified type 1 IFN-independent activities. Here, we show that STAT2 constitutively bound to STAT1, but not STAT3, via a conserved interface. While this interaction was irrelevant for type 1 interferon signaling and STAT1 activation, it precluded the nuclear translocation specifically of STAT1 in response to IFN-γ, interleukin-6 (IL-6), and IL-27. This is explained by the dimerization between activated STAT1 and unphosphorylated STAT2, whereby the semiphosphorylated dimers adopted a conformation incapable of importin-α binding. This, in turn, substantially attenuated cardinal IFN-γ responses, including MHC expression, senescence, and antiparasitic immunity, and shifted the transcriptional output of IL-27 from STAT1 to STAT3. Our results uncover STAT2 as a pervasive cytokine regulator due to its inhibition of STAT1 in multiple signaling pathways and provide an understanding of the type 1 interferon-independent activities of this protein.
Author Summary For more than a quarter century, we have known that STAT1 and STAT2 are essential for the classic host immune defense system against viral infections known as the type 1 interferon response. While STAT1 has since been assigned multiple additional roles, STAT2 is thought to function exclusively as the principal partner of STAT1 in the type 1 interferon system. However, patients and animals that are deficient in STAT2 show a surprisingly varied and sometimes subtle phenotype not fully accounted for by the known functions of this protein. Our investigations reveal an entirely novel facet of STAT2 action, namely as an innate inhibitor of STAT1 in its multiple biological roles. We identify the molecular mechanism of STAT1 inhibition and generate a novel biological tool with which we can dissociate STAT2’s activating and inhibitory effects on STAT1. We use this tool to show that STAT2 has major roles beyond antiviral protection, for example, in regulating cell proliferation and immune cell functions, as well as in killing intracellular parasites. These findings considerably expand our knowledge of STAT2 biology and necessitate a reassessment of regulatory mechanisms central to innate immunity and the therapeutic use of interferons.
Databáze: OpenAIRE
Externí odkaz: