title: TRIM4; a novel mitochondrial interacting RING E3 ligase, sensitizes the cells to hydrogen peroxide (H2O2) induced cell death.
abstract: The emerging evidences suggest that posttranslational modification of target protein by ubiquitin (Ub) not only regulate its turnover through ubiquitin proteasome system (UPS) but is a critical regulator of various signaling pathways. During ubiquitination, E3 ligase recognizes the target protein and determines the topology of ubiquitin chains. In current study, we studied the role of TRIM4, a member of the TRIM/RBCC protein family of RING E3 ligase, in regulation of hydrogen peroxide (H2O2) induced cell death. TRIM4 is expressed differentially in human tissues and expressed in most of the analyzed human cancer cell lines. The subcellular localization studies showed that TRIM4 forms distinct cytoplasmic speckle like structures which transiently interacts with mitochondria. The expression of TRIM4 induces mitochondrial aggregation and increased level of mitochondrial ROS in the presence of H2O2. It sensitizes the cells to H2O2 induced death whereas knockdown reversed the effect. TRIM4 potentiates the loss of mitochondrial transmembrane potential and cytochrome c release in the presence of H2O2. The analysis of TRIM4 interacting proteins showed its interaction with peroxiredoxin 1 (PRX1), including other proteins involved in regulation of mitochondrial and redox homeostasis. TRIM4 interaction with PRX1 is critical for the regulation of H2O2 induced cell death. Collectively, the evidences in the current study suggest the role of TRIM4 in regulation of oxidative stress induced cell death.
authors.affiliation: Department of Cell Biology, School of Biological Sciences and Biotechnology, Indian Institute of Advanced Research, Gandhinagar, India; Université de Bordeaux, Laboratoire Maladie Rares: Genetique et metabolisme, Hopital Pellegrin, 33076 Bordeaux, France.
authors.forename: Dhanendra
authors.initials: D
authors.lastname: Tomar
authors.affiliation: Department of Biochemistry, Faculty of Science, The M.S. University of Baroda, Vadodara 390002, Gujarat, India.
authors.forename: Paresh
authors.initials: P
authors.lastname: Prajapati
authors.affiliation: Université de Bordeaux, Laboratoire Maladie Rares: Genetique et metabolisme, Hopital Pellegrin, 33076 Bordeaux, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Lavie
authors.affiliation: Department of Biochemistry, Faculty of Science, The M.S. University of Baroda, Vadodara 390002, Gujarat, India.
authors.forename: Kritarth
authors.initials: K
authors.lastname: Singh
authors.affiliation: Department of Biochemistry, Faculty of Science, The M.S. University of Baroda, Vadodara 390002, Gujarat, India.
authors.forename: Sripada
authors.initials: S
authors.lastname: Lakshmi
authors.affiliation: Department of Biochemistry, Faculty of Science, The M.S. University of Baroda, Vadodara 390002, Gujarat, India.
authors.forename: Khyati
authors.initials: K
authors.lastname: Bhatelia
authors.affiliation: Department of Biochemistry, Faculty of Science, The M.S. University of Baroda, Vadodara 390002, Gujarat, India.
authors.forename: Milton
authors.initials: M
authors.lastname: Roy
authors.affiliation: Department of Cell Biology, School of Biological Sciences and Biotechnology, Indian Institute of Advanced Research, Gandhinagar, India.
authors.forename: Rochika
authors.initials: R
authors.lastname: Singh
authors.affiliation: Université de Bordeaux, Laboratoire Maladie Rares: Genetique et metabolisme, Hopital Pellegrin, 33076 Bordeaux, France. Electronic address: giovanni.benard@inserm.fr.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Bénard
authors.affiliation: Department of Biochemistry, Faculty of Science, The M.S. University of Baroda, Vadodara 390002, Gujarat, India. Electronic address: singhraj1975@gmail.com.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Singh
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D045304:Cytochromes c / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D057809:HEK293 Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D047468:Immunoprecipitation; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D016877:Oxidants / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects*; D040901:Proteomics; D012333:RNA, Messenger / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D025801:Ubiquitin / Q000378:metabolism; D054875:Ubiquitination / Q000187:drug effects
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D008565:Membrane Proteins; D016877:Oxidants; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; C114030:TRAT1 protein, human; D025801:Ubiquitin; D045304:Cytochromes c; D006861:Hydrogen Peroxide
keywords: Cell death; H(2)O(2); Mitochondria; PRX1; TRIM4; Ubiquitin E3 ligase