A STAT3 protein complex required for mitochondrial mRNA stability and cancer
C. Dilanka Fernando,
W. Samantha N. Jayasekara,
Chaitanya Inampudi,
Maija R.J. Kohonen-Corish,
Wendy A. Cooper,
Traude H. Beilharz,
Tracy M. Josephs,
Daniel J. Garama,
Daniel J. Gough
Affiliations
C. Dilanka Fernando
Department of Molecular Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, VIC 3800, Australia; Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, VIC 3168, Australia
W. Samantha N. Jayasekara
Department of Molecular Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, VIC 3800, Australia; Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, VIC 3168, Australia
Chaitanya Inampudi
Department of Molecular Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, VIC 3800, Australia; Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, VIC 3168, Australia
Maija R.J. Kohonen-Corish
Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia; Woolcock Institute of Medical Research, Glebe, NSW 2037, Australia; School of Medicine, Western Sydney University, Campbelltown, NSW 2560, Australia; Faculty of Science, UTS Sydney, Ultimo, NSW 2007, Australia
Wendy A. Cooper
School of Medicine, Western Sydney University, Campbelltown, NSW 2560, Australia; Tissue Pathology and Diagnostic Oncology, NSW Health Pathology, Royal Prince Alfred Hospital, Missenden Road, Camperdown, NSW 2050, Australia; Sydney Medical School, University of Sydney, Camperdown, NSW 2006, Australia
Traude H. Beilharz
Development and Stem Cells Program and the Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia
Tracy M. Josephs
Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia; ARC Centre for Cryo-Electron Microscopy of Membrane Proteins, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia
Daniel J. Garama
Department of Molecular Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, VIC 3800, Australia; Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, VIC 3168, Australia; Corresponding author
Daniel J. Gough
Department of Molecular Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, VIC 3800, Australia; Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, VIC 3168, Australia; Corresponding author
Summary: Signal transducer and activator of transcription 3 (STAT3) is a potent transcription factor necessary for life whose activity is corrupted in diverse diseases, including cancer. STAT3 biology was presumed to be entirely dependent on its activity as a transcription factor until the discovery of a mitochondrial pool of STAT3, which is necessary for normal tissue function and tumorigenesis. However, the mechanism of this mitochondrial activity remained elusive. This study uses immunoprecipitation and mass spectrometry to identify a complex containing STAT3, leucine-rich pentatricopeptide repeat containing (LRPPRC), and SRA stem-loop-interacting RNA-binding protein (SLIRP) that is required for the stability of mature mitochondrially encoded mRNAs and transport to the mitochondrial ribosome. Moreover, we show that this complex is enriched in patients with lung adenocarcinoma and that its deletion inhibits the growth of lung cancer in vivo, providing therapeutic opportunities through the specific targeting of the mitochondrial activity of STAT3.
