title: Role of Cathepsins in Mycobacterium tuberculosis Survival in Human Macrophages.
abstract: Cathepsins are proteolytic enzymes that function in the endocytic pathway, especially in lysosomes, where they contribute directly to pathogen killing or indirectly, by their involvement in the antigen presentation pathways. Mycobacterium tuberculosis (MTB) is a facultative intracellular pathogen that survives inside the macrophage phagosomes by inhibiting their maturation to phagolysosomes and thus avoiding a low pH and protease-rich environment. We previously showed that mycobacterial inhibition of the proinflammatory transcription factor NF-κB results in impaired delivery of lysosomal enzymes to phagosomes and reduced pathogen killing. Here, we elucidate how MTB also controls cathepsins and their inhibitors, cystatins, at the level of gene expression and proteolytic activity. MTB induced a general down-regulation of cathepsin expression in infected cells, and inhibited IFNγ-mediated increase of cathepsin mRNA. We further show that a decrease in cathepsins B, S and L favours bacterial survival within human primary macrophages. A siRNA knockdown screen of a large set of cathepsins revealed that almost half of these enzymes have a role in pathogen killing, while only cathepsin F coincided with MTB resilience. Overall, we show that cathepsins are important for the control of MTB infection, and as a response, it manipulates their expression and activity to favour its intracellular survival.
authors: Research Institute for Medicines, iMed-ULisboa, Faculty of Pharmacy, Universidade de Lisboa, Portugal.|Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Portugal.
authors: David
authors: D
authors: Pires
authors: Research Institute for Medicines, iMed-ULisboa, Faculty of Pharmacy, Universidade de Lisboa, Portugal.
authors: Joana
authors: J
authors: Marques
authors: Research Institute for Medicines, iMed-ULisboa, Faculty of Pharmacy, Universidade de Lisboa, Portugal.
authors: João Palma
authors: JP
authors: Pombo
authors: Research Institute for Medicines, iMed-ULisboa, Faculty of Pharmacy, Universidade de Lisboa, Portugal.|Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Portugal.
authors: Nuno
authors: N
authors: Carmo
authors: Research Institute for Medicines, iMed-ULisboa, Faculty of Pharmacy, Universidade de Lisboa, Portugal.|Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Portugal.
authors: Paulo
authors: P
authors: Bettencourt
authors: Centre National de la Recherche Scientifique, Institut de Pharmacologie et de Biologie Structurale, Toulouse, France.|Institut de Pharmacologie et de Biologie Structurale, Université de Toulouse, Université Paul Sabatier, Toulouse, France.
authors: Olivier
authors: O
authors: Neyrolles
authors: Centre National de la Recherche Scientifique, Institut de Pharmacologie et de Biologie Structurale, Toulouse, France.|Institut de Pharmacologie et de Biologie Structurale, Université de Toulouse, Université Paul Sabatier, Toulouse, France.
authors: Geanncarlo
authors: G
authors: Lugo-Villarino
authors: Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Portugal.
authors: Elsa
authors: E
authors: Anes
mesh_terms: D002403:Cathepsins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D015891:Cystatins / Q000235:genetics / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D054884:Host-Pathogen Interactions; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism* / Q000821:virology; D050296:Microbial Viability; D009169:Mycobacterium tuberculosis / Q000254:growth & development* / Q000502:physiology; D034622:RNA Interference
chemical_list: D015891:Cystatins; D007527:Isoenzymes; D002403:Cathepsins