title: Suppressive role of neddylation in dendritic cells during Mycobacterium tuberculosis infection.
abstract: Multiple strategies evolved by Mycobacterium tuberculosis (M. tb) have contributed to its successful prevalence. We previously identified specific genes in the cysteine protease and calcium-calmodulin pathways that regulated immune responses from dendritic cells (DCs). In this study we have characterized the role of neddylation in regulating various defense responses from DCs during mycobacterial infection. Neddylation is a process that is similar to ubiquitination. It however has its own enzyme machinery. It is coupled to ubiquitination and is important for maintaining cellular homeostasis. Here we show that stimulation of DCs with M. tb antigens Rv2463 and Rv3416 as well as infection with live M. tb modulates the expression levels of key proteins in the neddylation pathway. Further, stimulation with the two antigens promoted the association of NEDD8 with its target Cullin-1. The modulation in the expression levels of NEDD8 and SENtrin specific Protein 8 (SENP8) by the two antigens was in a calcium, MAPK and TLR dependent mechanism. Further, knockdown of specific genes of neddylation promoted the generation of oxidative burst, promoted phagolysosome fusion in mycobacteria infected DCs and induced higher expression of autophagy and apoptosis associated proteins in DCs. These results point toward a unique strategy employed by mycobacteria and its antigens towards immune suppression via modulating neddylation in DCs.
authors.affiliation: From the Infectious Disease Immunology Lab, Dr. B R Ambedkar Centre for Biomedical Research, University of Delhi, Delhi 110007, India. Electronic address: attinderchadha@gmail.com.
authors.forename: Attinder
authors.initials: A
authors.lastname: Chadha
authors.affiliation: From the Infectious Disease Immunology Lab, Dr. B R Ambedkar Centre for Biomedical Research, University of Delhi, Delhi 110007, India.
authors.forename: Subhash
authors.initials: S
authors.lastname: Mehto
authors.affiliation: From the Infectious Disease Immunology Lab, Dr. B R Ambedkar Centre for Biomedical Research, University of Delhi, Delhi 110007, 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 110007, India.
authors.forename: Mohit
authors.initials: M
authors.lastname: Vashishta
authors.affiliation: Allergy and Infectious Diseases Lab, Council of Scientific and Industrial Research-Institute of Genomics and Integrative Biology, Mall Road, Delhi 110007, India.
authors.forename: Shashank S
authors.initials: SS
authors.lastname: Kamble
authors.affiliation: Gut Biology Lab, Department of Zoology, University of Delhi, 110007, India.
authors.forename: Sonam
authors.initials: S
authors.lastname: Popli
authors.affiliation: Gut Biology Lab, Department of Zoology, University of Delhi, 110007, India.
authors.forename: Rajagopal
authors.initials: R
authors.lastname: Raman
authors.affiliation: Allergy and Infectious Diseases Lab, Council of Scientific and Industrial Research-Institute of Genomics and Integrative Biology, Mall Road, Delhi 110007, 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 110007, India. Electronic address: knatarajan@acbr.du.ac.in.
authors.forename: Krishnamurthy
authors.initials: K
authors.lastname: Natarajan
mesh_terms: D000818:Animals; D000942:Antigens, Bacterial / Q000276:immunology; D017209:Apoptosis; D001343:Autophagy; D020013:Calcium Signaling; D002478:Cells, Cultured; D044842:Cullin Proteins / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology; D005260:Female; D054884:Host-Pathogen Interactions; D008807:Mice, Inbred BALB C; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009169:Mycobacterium tuberculosis / Q000276:immunology / Q000472:pathogenicity*; D000075687:NEDD8 Protein; D010587:Phagocytosis; D011499:Protein Processing, Post-Translational; D034622:RNA Interference; D016897:Respiratory Burst; D051193:Toll-Like Receptors / Q000378:metabolism; D014162:Transfection; D014376:Tuberculosis / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology; D054875:Ubiquitination; D014452:Ubiquitins / Q000235:genetics / Q000378:metabolism*
chemical_list: D000942:Antigens, Bacterial; C100318:Cullin 1; D044842:Cullin Proteins; D000075687:NEDD8 Protein; C513172:Nedd8 protein, mouse; D051193:Toll-Like Receptors; D014452:Ubiquitins; D020928:Mitogen-Activated Protein Kinases
keywords: Immune response; Mycobacterium; Neddylation; Phagosome lysosome fusion; ROS