title: MITA modulated autophagy flux promotes cell death in breast cancer cells.
abstract: The crosstalk between inflammation and autophagy is an emerging phenomenon observed during tumorigenesis. Activation of NF-κB and IRF3 plays a key role in the regulation of cytokines that are involved in tumor growth and progression. The genes of innate immunity are known to regulate the master transcription factors like NF-κB and IRF3. Innate immunity pathways at the same time regulate the genes of the autophagy pathway which are essential for tumor cell metabolism. In the current study, we studied the role of MITA (Mediator of IRF3 Activation), a regulator of innate immunity, in the regulation of autophagy and its implication in cell death of breast cancer cells. Here, we report that MITA inhibits the fusion of autophagosome with lysosome as evident from different autophagy flux assays. The expression of MITA induces the translocation of p62 and NDP52 to mitochondria which further recruits LC3 for autophagosome formation. The expression of MITA decreased mitochondrial number and enhances mitochondrial ROS by increasing complex-I activity. The enhancement of autophagy flux with rapamycin or TFEB expression normalized MITA induced cell death. The evidences clearly show that MITA regulates autophagy flux and modulates mitochondrial turnover through mitophagy.
authors.affiliation: Department of Biochemistry, Faculty of Science, The Maharaja Sayajirao University of Baroda, Sayajigunj, Vadodara 390002, Gujarat, India.
authors.forename: Khyati
authors.initials: K
authors.lastname: Bhatelia
authors.affiliation: Department of Biochemistry, Faculty of Science, The Maharaja Sayajirao University of Baroda, Sayajigunj, Vadodara 390002, Gujarat, India.
authors.forename: Kritarth
authors.initials: K
authors.lastname: Singh
authors.affiliation: Department of Biochemistry, Faculty of Science, The Maharaja Sayajirao University of Baroda, Sayajigunj, Vadodara 390002, Gujarat, India.
authors.forename: Paresh
authors.initials: P
authors.lastname: Prajapati
authors.affiliation: Department of Biochemistry, Faculty of Science, The Maharaja Sayajirao University of Baroda, Sayajigunj, Vadodara 390002, Gujarat, India.
authors.forename: Lakshmi
authors.initials: L
authors.lastname: Sripada
authors.affiliation: Department of Biochemistry, Faculty of Science, The Maharaja Sayajirao University of Baroda, Sayajigunj, Vadodara 390002, Gujarat, India.
authors.forename: Milton
authors.initials: M
authors.lastname: Roy
authors.affiliation: Department of Biochemistry, Faculty of Science, The Maharaja Sayajirao University of Baroda, Sayajigunj, Vadodara 390002, Gujarat, India. Electronic address: rajesh.singh-biochem@msubaroda.ac.in.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Singh
mesh_terms: D000071182:Autophagosomes / Q000378:metabolism; D001343:Autophagy / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D063646:Carcinogenesis / Q000235:genetics*; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D007249:Inflammation / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D050838:Interferon Regulatory Factor-3 / Q000235:genetics* / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D063306:Mitophagy / Q000235:genetics; D016328:NF-kappa B / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D020123:Sirolimus / Q000008:administration & dosage; D000099197:STING Protein
chemical_list: D050838:Interferon Regulatory Factor-3; D008565:Membrane Proteins; D016328:NF-kappa B; D020123:Sirolimus; C494232:IRF3 protein, human; C532857:STING1 protein, human; D000099197:STING Protein
keywords: Autophagy flux; Breast cancer; Inflammation; MITA; Mitophagy