Peptide inhibition of p22phox and Rubicon interaction as a therapeutic strategy for septic shock.
Sepsis is a clinical syndrome that complicates severe infection and is characterized by the systemic inflammatory response syndrome (SIRS), is a life threatening disease characterized by inflammation of the entire body. Upon microbial infection, p22phox-gp91phox NADPH oxidase (NOX) complexes produce reactive oxygen species (ROS) that are critical for the elimination of invading microbes. However, excess production of ROS represents a key element in the cascade of deleterious processes in sepsis. We have previously reported direct crosstalk between autophagy and phagocytosis machineries by demonstrating that the Rubicon protein interacts with p22phox upon microbial infection, facilitating phagosomal trafficking of the p22phox-gp91phox NOX complex to induce a ROS burst, inflammatory cytokine production, and thereby, potent anti-microbial activities. Here, we showed N8 peptide, an N-terminal 8-amino acid peptide derived from p22phox, was sufficient for Rubicon interaction and thus, capable of robustly blocking the Rubicon-p22phox interaction and profoundly suppressing ROS and inflammatory cytokine production. Consequently, treatment with the Tat-N8 peptide or a N8 peptide-mimetic small-molecule dramatically reduced the mortality associated with Cecal-Ligation-and-Puncture-induced polymicrobial sepsis in mice. This study demonstrates a new anti-sepsis therapeutic strategy by blocking the crosstalk between autophagy and phagocytosis innate immunity machineries, representing a potential paradigm shift for urgently needed therapeutic intervention against this life-threatening SIRS.
Department of Molecular and Life Science, College of Science and Technology, Hanyang University, Ansan 15588, South Korea.
Ye-Ram
YR
Kim
Department of Molecular and Life Science, College of Science and Technology, Hanyang University, Ansan 15588, South Korea.
Hyun-Jung
HJ
Koh
Department of Molecular and Life Science, College of Science and Technology, Hanyang University, Ansan 15588, South Korea.
Jae-Sung
JS
Kim
Department of Molecular and Life Science, College of Science and Technology, Hanyang University, Ansan 15588, South Korea.
Jin-Seung
JS
Yun
Department of Pathology, College of Medicine, Hanyang University, Seoul 04763, South Korea.
Kiseok
K
Jang
Korea Chemical Bank, Korea Research Institute of Chemical Technology, Daejeon 34114, South Korea.
Joo-Youn
JY
Lee
Department of Molecular Microbiology and Immunology, University of Southern California, Keck School of Medicine, Los Angeles, CA 90033, USA.
Jae U
JU
Jung
Department of Molecular and Life Science, College of Science and Technology, Hanyang University, Ansan 15588, South Korea. Electronic address: chulsuyang@hanyang.ac.kr.
Chul-Su
CS
Yang
D000818:Animals; D002460:Cell Line; D003573:Cytochrome b Group / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D010455:Peptides / Q000737:chemistry / Q000627:therapeutic use*; D060066:Protein Interaction Maps / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism; D012772:Shock, Septic / Q000188:drug therapy* / Q000378:metabolism
D003573:Cytochrome b Group; D016207:Cytokines; D047908:Intracellular Signaling Peptides and Proteins; D010455:Peptides; D017382:Reactive Oxygen Species; C000601571:Rubcn protein, mouse; D019255:NADPH Oxidases; C515614:Cyba protein, mouse
Inflammation; Reactive oxygen species; Rubicon; Sepsis; p22phox