Background:PhoP is global regulator of Mycobacterium tuberculosis physiology. However, the role of phosphorylation of PhoP remains unknown. Results: PhoP activates complex lipid biosynthesis only upon phosphorylation. Conclusion: PhoP regulates lipid biosynthesis by a phosphorylation-dependent mechanism to contribute to morphology of the bacilli. Significance: This study sheds light on the unexplored role of phosphorylation of PhoP in regulating biosynthesis of lipids unique to M. tuberculosis.

SummaryThe co-ordinated regulation of heat shock proteins is critically important for the stress response of M. tuberculosis, failure of which results in enhanced immune recognition of the tubercle bacilli with reduced survival during chronic infections. In this study, we show that PhoP regulates the transcription of α-crystallin 2 (acr2), expression of which increases more than any other gene of M. tuberculosis during heat-shock or following macrophage infection. We also show that regulation of acr2 by PhoP is attributable to direct regulator-promoter interactions at specific sites proximal to a sequence motif comprising the target site of another virulence factor, HspR. While both these regulators, on their own, are capable of influencing acr2 expression, remarkably our results show that the two virulence regulators PhoP and HspR interact with each other to influence their in vivo recruitment at the acr2 regulatory region, and in turn, contribute to stressspecific regulation of acr2 expression. We propose a model to suggest how protein-protein interactions between PhoP and HspR influence the regulation of α-crystallin 2, an essential pathogenic determinant of M. tuberculosis.

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Nitric oxide (NO) is a gaseous diatomic molecule with a wide variety of physiological and pathological implications in plants. Presence of unpaired electron in its molecular orbital makes it highly reactive; it can react directly with metal complexes, radicals, DNA, proteins, lipids and other biomolecules. Nitric oxide (NO) and reactive oxygen species (ROS) are known to play essential role in a number of important plant physiological processes. This manuscript reviews the role of NO on these processes during various biotic and abiotic stresses.

Summary Galunisertib (LY2157299) is a selective ATP-mimetic inhibitor of TGF-β receptor-I activation, currently under clinical trial in a variety of cancers. We have tested the combined effects of galunisertib- and interleukin-15-activated dendritic cells in an aggressive and highly metastatic murine lymphoma. Based on the tumor-draining lymph node architecture, and its histology, the combination therapy results in better prognosis, including disappearance of the disease-exacerbating regulatory T cells. Our data suggest that galunisertib significantly enhances the success of immunotherapy with IL-15-activated dendritic cells by limiting the regulatory T cells generation with consequent downregulation of regulatory T cells in the tumor-draining lymph nodes and vascularized organ like spleen. This is also associated with consistent loss p-SMAD2 and downregulation of Neuropilin-1, leading to better prognosis and positive outcome. These results connect the role of combined therapy with the consequent elimination of disease-exacerbating T regulatory cells in a metastatic murine lymphoma.