Hypoxia increases persulfide and polysulfide formation by AMP kinase dependent cystathionine gamma lyase phosphorylation
Shafiul Alam,
Sibile Pardue,
Xinggui Shen,
John D. Glawe,
Takashi Yagi,
Mohammad Alfrad Nobel Bhuiyan,
Rakesh P. Patel,
Paari S. Dominic,
Chiranjiv S. Virk,
Md Shenuarin Bhuiyan,
A. Wayne Orr,
Chad Petit,
Gopi K. Kolluru,
Christopher G. Kevil
Affiliations
Shafiul Alam
Department of Pathology, LSU Health Sciences Center, Shreveport, USA
Sibile Pardue
Department of Pathology, LSU Health Sciences Center, Shreveport, USA
Xinggui Shen
Department of Pathology, LSU Health Sciences Center, Shreveport, USA
John D. Glawe
Department of Pathology, LSU Health Sciences Center, Shreveport, USA
Takashi Yagi
Department of Pathology, LSU Health Sciences Center, Shreveport, USA
Mohammad Alfrad Nobel Bhuiyan
Internal Medicine, LSU Health Sciences Center, Shreveport, USA
Rakesh P. Patel
Department of Pathology, University of Alabama at Birmingham, USA
Paari S. Dominic
Internal Medicine-Cardiovascular Medicine, University of Iowa Healthcare, Iowa, USA
Chiranjiv S. Virk
Department of Surgery, LSU Health Sciences Center, Shreveport, USA
Md Shenuarin Bhuiyan
Department of Pathology, LSU Health Sciences Center, Shreveport, USA
A. Wayne Orr
Department of Pathology, LSU Health Sciences Center, Shreveport, USA
Chad Petit
Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, USA
Gopi K. Kolluru
Department of Pathology, LSU Health Sciences Center, Shreveport, USA
Christopher G. Kevil
Department of Pathology, LSU Health Sciences Center, Shreveport, USA; Department of Cellular Biology and Anatomy, LSU Health Sciences Center, Shreveport, USA; Department of Molecular and Cellular Physiology, LSU Health Sciences Center, Shreveport, USA; Corresponding author. Department of Pathology, LSU Health Sciences Center, Shreveport, LA, 71130, USA.
Hydropersulfide and hydropolysulfide metabolites are increasingly important reactive sulfur species (RSS) regulating numerous cellular redox dependent functions. Intracellular production of these species is known to occur through RSS interactions or through translational mechanisms involving cysteinyl t-RNA synthetases. However, regulation of these species under cell stress conditions, such as hypoxia, that are known to modulate RSS remain poorly understood. Here we define an important mechanism of increased persulfide and polysulfide production involving cystathionine gamma lyase (CSE) phosphorylation at serine 346 and threonine 355 in a substrate specific manner, under acute hypoxic conditions. Hypoxic phosphorylation of CSE occurs in an AMP kinase dependent manner increasing enzyme activity involving unique inter- and intramolecular interactions within the tetramer. Importantly, both cellular hypoxia and tissue ischemia result in AMP Kinase dependent CSE phosphorylation that regulates blood flow in ischemic tissues. Our findings reveal hypoxia molecular signaling pathways regulating CSE dependent persulfide and polysulfide production impacting tissue and cellular response to stress.
