title: Mycobacterium tuberculosis-triggered Hippo pathway orchestrates CXCL1/2 expression to modulate host immune responses.
abstract: Mycobacterium tuberculosis (Mtb) pathogenesis encompasses a plethora of finely regulated alterations within the host which eventually coin the outcome of infection. Chemokines are important components in directing immune cell recruitment to the site of infection, and shaping the disease progression. Here, we demonstrate that Hippo (mammalian sterile 20-like 1 and 2 kinases, MST1/2, in mammals), is activated during mycobacterial infection in a toll-like receptor (TLR) 2-interleukin receptor-1 associated kinases (IRAK1/4)-dependent manner. Mtb-triggered Hippo signaling modulates the expression and secretion of chemokines (CXCL1 and CXCL2); as silencing MST1/2 compromised the ability of Mtb to furnish the same. Further insight into the mechanism of Hippo-mediated regulation of chemokines revealed the role for a non-canonical Hippo effector interferon (IFN) regulatory factor (IRF) 3 in the process and marked the effect to be independent of LATS1. Alongside their ability to guide directed recruitment of immune cells, we have uncovered a paracrine role for Hippo-mediated secretion of CXCL1 and CXCL2 in the production of anti-microbial peptides (beta-defensins), iNOS, NOX2 and pro-inflammatory molecules during mycobacterial infection of the host. This study highlights the involvement of TLR2-IRAK1/4-MST1/2-IRF3 axis in Mtb-triggered modulation of chemokines and identifies Hippo signaling as a novel regulator of host-mycobacterial interactions.
authors.affiliation: Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore 560012, Karnataka, India.
authors.forename: Monoranjan
authors.initials: M
authors.lastname: Boro
authors.affiliation: Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore 560012, Karnataka, India.
authors.forename: Vikas
authors.initials: V
authors.lastname: Singh
authors.affiliation: Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore 560012, Karnataka, India.
authors.forename: Kithiganahalli Narayanaswamy
authors.initials: KN
authors.lastname: Balaji
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D054360:Chemokine CXCL1 / Q000378:metabolism*; D054426:Chemokine CXCL2 / Q000378:metabolism*; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D000090683:Hippo Signaling Pathway; D054884:Host-Pathogen Interactions / Q000276:immunology*; D006801:Humans; D007109:Immunity; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism; D053592:Interleukin-1 Receptor-Associated Kinases / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D051379:Mice; D009169:Mycobacterium tuberculosis / Q000502:physiology*; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D000090742:Serine-Threonine Kinase 3; D015398:Signal Transduction; D051195:Toll-Like Receptor 2 / Q000378:metabolism; D000099317:Hippo Kinases
chemical_list: D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; D017228:Hepatocyte Growth Factor; D050838:Interferon Regulatory Factor-3; D053592:Interleukin-1 Receptor-Associated Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D000090742:Serine-Threonine Kinase 3; D051195:Toll-Like Receptor 2; C494233:Irf3 protein, mouse; C082332:macrophage stimulating protein; C490501:Lats1 protein, mouse; C507769:Irak1 protein, mouse; C507774:Irak4 protein, mouse; C490818:Stk3 protein, mouse; D000099317:Hippo Kinases