Regulation of L-type Voltage Gated Calcium Channel CACNA1S in Macrophages upon Mycobacterium tuberculosis Infection.
We demonstrated earlier the inhibitory role played by Voltage Gated Calcium Channels (VGCCs) in regulating Mycobacterium tuberculosis (M. tb) survival and pathogenesis. In this report, we investigated mechanisms and key players that regulate the surface expression of VGCC-CACNA1S by Rv2463 and M. tb infection in macrophages. Our earlier work identified Rv2463 to be expressed at early times post infection in macrophages that induced suppressor responses to dendritic cells and macrophages. Our results in this study demonstrate a role of MyD88 independent TLR pathway in mediating CACNA1S expression. Dissecting the role for second messengers, we show that calcium homeostasis plays a key role in CACNA1S expression during M. tb infection. Using siRNAs against molecular sensors of calcium regulation, we show an involvement of ER associated Stromal Interaction Molecules 1 and 2 (STIM1 and STIM2), and transcription factor pCREB, towards CACNA1S expression that also involved the MyD88 independent pathway. Interestingly, reactive oxygen species played a negative role in M. tb mediated CACNA1S expression. Further, a cross-regulation of ROS and pCREB was noted that governed CACNA1S expression. Characterizing the mechanisms governing CACNA1S expression would improve our understanding of the regulation of VGCC expression and its role in M. tb pathogenesis during M. tb infection.
Infectious Disease Immunology Lab, Dr. B. R. Ambedkar Centre for Biomedical Research, University of Delhi, Delhi, 110007, India.
Cecil
C
Antony
Infectious Disease Immunology Lab, Dr. B. R. Ambedkar Centre for Biomedical Research, University of Delhi, Delhi, 110007, India.
Subhash
S
Mehto
CSIR-Institute of Genomics and Integrative Biology, Mall Road, Delhi, 110007, India.
Brijendra K
BK
Tiwari
CSIR-Institute of Genomics and Integrative Biology, Mall Road, Delhi, 110007, India.
Yogendra
Y
Singh
Infectious Disease Immunology Lab, Dr. B. R. Ambedkar Centre for Biomedical Research, University of Delhi, Delhi, 110007, India.
Krishnamurthy
K
Natarajan
D000818:Animals; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism*; D020746:Calcium Channels, L-Type; D015815:Cell Adhesion Molecules / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005434:Flow Cytometry; D015870:Gene Expression; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D016897:Respiratory Burst / Q000235:genetics; D015398:Signal Transduction; D000071737:Stromal Interaction Molecule 1; D000071738:Stromal Interaction Molecule 2; D014157:Transcription Factors / Q000378:metabolism; D014376:Tuberculosis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism* / Q000382:microbiology
C412223:CACNA1S protein, human; D015220:Calcium Channels; D020746:Calcium Channels, L-Type; D015815:Cell Adhesion Molecules; D017362:Cyclic AMP Response Element-Binding Protein; D008565:Membrane Proteins; D053594:Myeloid Differentiation Factor 88; D009363:Neoplasm Proteins; D017382:Reactive Oxygen Species; C103530:STIM1 protein, human; C513279:STIM2 protein, human; D000071737:Stromal Interaction Molecule 1; D000071738:Stromal Interaction Molecule 2; D014157:Transcription Factors; D002118:Calcium