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.