title: Reciprocal regulation of reactive oxygen species and phospho-CREB regulates voltage gated calcium channel expression during Mycobacterium tuberculosis infection.
abstract: Our previous work has demonstrated the roles played by L-type Voltage Gated Calcium Channels (VGCC) in regulating Mycobacterium tuberculosis (M. tb) survival and pathogenesis. Here we decipher mechanisms and pathways engaged by the pathogen to regulate VGCC expression in macrophages. We show that M. tb and its antigen Rv3416 use phospho-CREB (pCREB), Reactive Oxygen Species (ROS), Protein Kinase C (PKC) and Mitogen Activated Protein Kinase (MAPK) to modulate VGCC expression in macrophages. siRNA mediated knockdown of MyD88, IRAK1, IRAK2 or TRAF6 significantly inhibited antigen mediated VGCC expression. Inhibiting Protein Kinase C (PKC) or MEK-ERK1/2 further increased VGCC expression. Interestingly, inhibiting intracellular calcium release upregulated antigen mediated VGCC expression, while inhibiting extracellular calcium influx had no significant effect. siRNA mediated knockdown of transcription factors c-Jun, SOX5 and CREB significantly inhibited Rv3416 mediated VGCC expression. A dynamic reciprocal cross-regulation between ROS and pCREB was observed that in turn governed VGCC expression with ROS playing a limiting role in the process. Further dissection of the mechanisms such as the interplay between ROS and pCREB would improve our understanding of the regulation of VGCC expression during M. tb infection.
authors.affiliation: From the Infectious Disease Immunology Lab, Dr. B. R. Ambedkar Centre for Biomedical Research, University of Delhi, Delhi, India.
authors.forename: Arti
authors.initials: A
authors.lastname: Selvakumar
authors.affiliation: From the Infectious Disease Immunology Lab, Dr. B. R. Ambedkar Centre for Biomedical Research, University of Delhi, Delhi, India.
authors.forename: Cecil
authors.initials: C
authors.lastname: Antony
authors.affiliation: From the Infectious Disease Immunology Lab, Dr. B. R. Ambedkar Centre for Biomedical Research, University of Delhi, Delhi, India.
authors.forename: Jhalak
authors.initials: J
authors.lastname: Singhal
authors.affiliation: CSIR-Institute of Genomics and Integrative Biology, Delhi, India.
authors.forename: Brijendra K
authors.initials: BK
authors.lastname: Tiwari
authors.affiliation: CSIR-Institute of Genomics and Integrative Biology, Delhi, India.
authors.forename: Yogendra
authors.initials: Y
authors.lastname: Singh
authors.affiliation: From the Infectious Disease Immunology Lab, Dr. B. R. Ambedkar Centre for Biomedical Research, University of Delhi, Delhi, India.
authors.forename: Krishnamurthy
authors.initials: K
authors.lastname: Natarajan
mesh_terms: D000942:Antigens, Bacterial / Q000502:physiology; D015220:Calcium Channels / Q000378:metabolism*; D002460:Cell Line; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D006801:Humans; D008264:Macrophages / Q000378:metabolism; D053858:Metabolic Networks and Pathways / Q000276:immunology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism / Q000502:physiology; D009169:Mycobacterium tuberculosis / Q000378:metabolism* / Q000472:pathogenicity; D011493:Protein Kinase C / Q000378:metabolism / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D000942:Antigens, Bacterial; D015220:Calcium Channels; D017362:Cyclic AMP Response Element-Binding Protein; D017382:Reactive Oxygen Species; D011493:Protein Kinase C; D020928:Mitogen-Activated Protein Kinases