IFN-γ-inducible antiviral responses require ULK1-mediated activation of MLK3 and ERK5

Diana Saleiro; Gavin T Blyth; Ewa M Kosciuczuk; Patrick A Ozark; Beata Majchrzak-Kita; Ahmet D Arslan; Mariafausta Fischietti; Neha K Reddy; Curt M Horvath; Roger J Davis; Eleanor N Fish; Leonidas C Platanias

doi:10.1126/scisignal.aap9921

IFN-γ-inducible antiviral responses require ULK1-mediated activation of MLK3 and ERK5

Sci Signal. 2018 Nov 20;11(557):eaap9921. doi: 10.1126/scisignal.aap9921.

Authors

Diana Saleiro¹, Gavin T Blyth¹, Ewa M Kosciuczuk^{1

2}, Patrick A Ozark^{3

4}, Beata Majchrzak-Kita^{5

6}, Ahmet D Arslan¹, Mariafausta Fischietti¹, Neha K Reddy¹, Curt M Horvath⁷, Roger J Davis^{8

9}, Eleanor N Fish^{5

6}, Leonidas C Platanias^{10

2}

Affiliations

¹ Robert H. Lurie Comprehensive Cancer Center and Division of Hematology-Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
² Division of Hematology-Oncology, Department of Medicine, Jesse Brown Veterans Affairs Medical Center, Chicago, IL 60612, USA.
³ Simpson Querrey Center for Epigenetics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
⁴ Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
⁵ Toronto General Hospital Research Institute, University Health Network, Toronto, ON M5G 2MI, Canada.
⁶ Department of Immunology, University of Toronto, Toronto, ON M5G 2MI, Canada.
⁷ Department of Molecular Biosciences, Northwestern University, Evanston, IL 60208, USA.
⁸ Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
⁹ Howard Hughes Medical Institute, Worcester, MA 01605, USA.
¹⁰ Robert H. Lurie Comprehensive Cancer Center and Division of Hematology-Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA. l-platanias@northwestern.edu.

Abstract

It is well established that activation of the transcription factor signal transducer and activator of transcription 1 (STAT1) is required for the interferon-γ (IFN-γ)-mediated antiviral response. Here, we found that IFN-γ receptor stimulation also activated Unc-51-like kinase 1 (ULK1), an initiator of Beclin-1-mediated autophagy. Furthermore, the interaction between ULK1 and the mitogen-activated protein kinase kinase kinase MLK3 (mixed lineage kinase 3) was necessary for MLK3 phosphorylation and downstream activation of the kinase ERK5. This autophagy-independent activity of ULK1 promoted the transcription of key antiviral IFN-stimulated genes (ISGs) and was essential for IFN-γ-dependent antiviral effects. These findings define a previously unknown IFN-γ pathway that appears to be a key element of the antiviral response.

Publication types

Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Autophagy
Autophagy-Related Protein-1 Homolog / metabolism*
Beclin-1 / metabolism
Cell Line, Tumor
Class III Phosphatidylinositol 3-Kinases / metabolism
Cytokines / metabolism
Gene Expression Profiling
Humans
Immunity, Innate
Interferon gamma Receptor
Interferon-gamma / metabolism*
Intracellular Signaling Peptides and Proteins / metabolism*
MAP Kinase Kinase Kinases / metabolism*
Mice
Mitogen-Activated Protein Kinase 7 / metabolism*
Mitogen-Activated Protein Kinase Kinase Kinase 11
Multigene Family
Phosphorylation
Protein Binding
Receptors, Interferon / metabolism
Recombinant Proteins / metabolism
Signal Transduction
Transcription, Genetic
U937 Cells
Virus Diseases / metabolism

Substances

BECN1 protein, human
Beclin-1
Cytokines
IFNG protein, human
Intracellular Signaling Peptides and Proteins
Receptors, Interferon
Recombinant Proteins
Interferon-gamma
Class III Phosphatidylinositol 3-Kinases
Autophagy-Related Protein-1 Homolog
ULK1 protein, human
MAPK7 protein, human
Mitogen-Activated Protein Kinase 7
MAP Kinase Kinase Kinases

Abstract

Publication types

MeSH terms

Substances

Grants and funding