E3 ligase subunit Fbxo15 and PINK1 kinase regulate cardiolipin synthase 1 stability and mitochondrial function in pneumonia.
Acute lung injury (ALI) is linked to mitochondrial injury, resulting in impaired cellular oxygen utilization; however, it is unknown how these events are linked on the molecular level. Cardiolipin, a mitochondrial-specific lipid, is generated by cardiolipin synthase (CLS1). Here, we show that S. aureus activates a ubiquitin E3 ligase component, Fbxo15, that is sufficient to mediate proteasomal degradation of CLS1 in epithelia, resulting in decreased cardiolipin availability and disrupted mitochondrial function. CLS1 is destabilized by the phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK1), which binds CLS1 to phosphorylate and regulates CLS1 disposal. Like Fbxo15, PINK1 interacts with and regulates levels of CLS1 through a mechanism dependent upon Thr219. S. aureus infection upregulates this Fbxo15-PINK1 pathway to impair mitochondrial integrity, and Pink1 knockout mice are less prone to S. aureus-induced ALI. Thus, ALI-associated disruption of cellular bioenergetics involves bioeffectors that utilize a phosphodegron to elicit ubiquitin-mediated disposal of a key mitochondrial enzyme.
Department of Medicine, Acute Lung Injury Center of Excellence, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Bill B
BB
Chen
Department of Medicine, Acute Lung Injury Center of Excellence, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Tiffany A
TA
Coon
Department of Medicine, Acute Lung Injury Center of Excellence, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Jennifer R
JR
Glasser
Department of Medicine, Acute Lung Injury Center of Excellence, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Chunbin
C
Zou
Department of Medicine, Acute Lung Injury Center of Excellence, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Bryon
B
Ellis
Department of Medicine, Acute Lung Injury Center of Excellence, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Tuhin
T
Das
Department of Medicine, Acute Lung Injury Center of Excellence, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Alison C
AC
McKelvey
Department of Medicine, Acute Lung Injury Center of Excellence, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Shristi
S
Rajbhandari
Department of Medicine, Acute Lung Injury Center of Excellence, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Travis
T
Lear
Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Christelle
C
Kamga
Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Sruti
S
Shiva
Department of Neurology, Mt. Sinai School of Medicine, New York, NY 10029, USA.
Chenjian
C
Li
Department of Medicine, Acute Lung Injury Center of Excellence, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Joseph M
JM
Pilewski
Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Jason
J
Callio
Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Charleen T
CT
Chu
Department of Medicine, Acute Lung Injury Center of Excellence, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Anuradha
A
Ray
Department of Medicine, Acute Lung Injury Center of Excellence, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Prabir
P
Ray
Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Yulia Y
YY
Tyurina
Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Valerian E
VE
Kagan
Department of Medicine, Acute Lung Injury Center of Excellence, University of Pittsburgh, Pittsburgh, PA 15213, USA; Department of Cell Biology and Physiology, University of Pittsburgh, Pittsburgh, PA 15213, USA; Medical Specialty Service Line, Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, PA 15240, USA. Electronic address: mallampallirk@upmc.edu.
Rama K
RK
Mallampalli
D000293:Adolescent; D000328:Adult; D000818:Animals; D051940:B7-2 Antigen / Q000235:genetics / Q000378:metabolism*; D016022:Case-Control Studies; D002460:Cell Line; D002478:Cells, Cultured; D002648:Child; D004795:Enzyme Stability; D044783:F-Box Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism*; D011014:Pneumonia / Q000378:metabolism*; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D000099202:PTEN-Induced Putative Kinase
D051940:B7-2 Antigen; D044783:F-Box Proteins; D011494:Protein Kinases; D021122:Protein Subunits; D000099202:PTEN-Induced Putative Kinase; C497965:Cd86 protein, mouse; C518314:Fbx15 protein, mouse