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The Mycobacterium tuberculosis exported repetitive protein (RvErp) is a crucial virulence-associated factor as determined by its role in the survival and multiplication of mycobacteria in cultured macrophages and in vivo. Although attempts have been made to understand the function of Erp protein, its exact role in Mycobacterium pathogenesis is still elusive. One way to determine this is by searching for novel interactions of RvErp. Using a yeast two-hybrid assay, an adenylyl cyclase (AC), Rv2212, was found to interact with RvErp. The interaction between RvErp and Rv2212 is direct and occurs at the endogenous level. The Erp protein of Mycobacterium smegmatis (MSMEG_6405, or MsErp) interacts neither with Rv2212 nor with Ms_4279, the M. smegmatis homologue of Rv2212. Deletion mutants of Rv2212 revealed its adenylyl cyclase domain to be responsible for the interaction. RvErp enhances Rv2212-mediated cyclic AMP (cAMP) production. Also, the biological significance of the interaction between RvErp and Rv2212 was demonstrated by the enhanced survival of M. smegmatis within THP-1 macrophages. Taken together, these studies address a novel mechanism by which Erp executes its function. IMPORTANCE RvErp is one of the important virulence factors of M. tuberculosis. This study describes a novel function of RvErp protein of M. tuberculosis by identifying Rv2212 as its interacting protein.Rv2212 is an adenylyl cyclase (AC) and produces cAMP, one of the prime second messengers that regulate the intracellular survival of mycobacteria. Therefore, the significance of investigating novel interactions of RvErp is paramount in unraveling the mechanisms governing the intracellular survival of mycobacteria. Discerning the molecular mechanisms used by specific mycobacterial proteins involved in infection and virulence requires an understanding of the protein-protein interaction network. The interactions of secretory proteins of Mycobacterium with the host machinery are vital for successful infection. One such secretory protein involved in virulence of Mycobacterium tuberculosis is Erp (Rv3810).The erp gene of M. tuberculosis encodes an ϳ28.0-kDa secretory protein that migrates as a 36.0-kDa protein and is present in all species of mycobacteria. Its disruption results in a marked decrease in virulence, with lower levels of survival not only in in vitro and cell culture assays but also under in vivo conditions (1, 2). It was recently shown that the nature of the erp allele strongly affects the number and the size of the lung lesions in infected animals (3). No homologue of Erp has been found in other bacterial species, making Erp a mycobacterial signature (4).Erp has a composite structure made up of three domains. While the amino-terminal domain (amino acids 1 to 80) and the carboxyterminal domain (amino acids 176 to 284) are conserved, the central domain, consisting of tandem repeats of 5 amino acids based on a PGLTS motif, is subjected to a high level of interspecies variability (1). A signal sequence is present in the amino termi...

Major histocompatibility class I (MHC-I) proteins mediate immunosurveillance against pathogens and cancers by presenting antigenic or mutated peptides to antigen receptors of CD8+ T cells and by engaging receptors of natural killer (NK) cells. In humans, MHC-I molecules are highly polymorphic. MHC-I variations permit the display of thousands of distinct peptides at the cell surface. Recent mass spectrometric studies have revealed unique and shared characteristics of the peptidomes of individual MHC-I variants. The cell surface expression of MHC-I–peptide complexes requires the functions of many intracellular assembly factors, including the transporter associated with antigen presentation (TAP), tapasin, calreticulin, ERp57, TAP-binding protein related (TAPBPR), endoplasmic reticulum aminopeptidases (ERAPs), and the proteasomes. Recent studies provide important insights into the structural features of these factors that govern MHC-I assembly as well as the mechanisms underlying peptide exchange. Conformational sensing of MHC-I molecules mediates the quality control of intracellular MHC-I assembly and contributes to immune recognition by CD8 at the cell surface. Recent studies also show that several MHC-I variants can follow unconventional assembly routes to the cell surface, conferring selective immune advantages that can be exploited for immunotherapy.