Department of Biochemistry
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Browsing Department of Biochemistry by Author "Afroz, Sumbul"
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ItemAmino acid starvation sensing dampens IL-1β production by activating riboclustering and autophagy( 2018-04-05) Battu, Srikanth ; Afroz, Sumbul ; Giddaluru, Jeevan ; Naz, Saima ; Huang, Weishan ; Khumukcham, Saratchandra Singh ; Khan, Rafiq Ahmad ; Bhat, Saleem Yousuf ; Qureshi, Insaf Ahmed ; Manavathi, Bramanandam ; Khan, Aleem Ahmed ; August, Avery ; Hasnain, Seyed Ehtesham ; Khan, NooruddinActivation of the amino acid starvation response (AAR) increases lifespan and acute stress resistance as well as regulates inflammation. However, the underlying mechanisms remain unclear. Here, we show that activation of AAR pharmacologically by Halofuginone (HF) significantly inhibits production of the proinflammatory cytokine interleukin 1β (IL-1β) and provides protection from intestinal inflammation in mice. HF inhibits IL-1β through general control nonderepressible 2 kinase (GCN2)–dependent activation of the cytoprotective integrated stress response (ISR) pathway, resulting in rerouting of IL-1β mRNA from translationally active polysomes to inactive ribocluster complexes—such as stress granules (SGs)—via recruitment of RNA-binding proteins (RBPs) T cell–restricted intracellular antigen-1(TIA-1)/TIA-1–related (TIAR), which are further cleared through induction of autophagy. GCN2 ablation resulted in reduced autophagy and SG formation, which is inversely correlated with IL-1β production. Furthermore, HF diminishes inflammasome activation through suppression of reactive oxygen species (ROS) production. Our study unveils a novel mechanism by which IL-1β is regulated by AAR and further suggests that administration of HF might offer an effective therapeutic intervention against inflammatory diseases.
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ItemImmunogenic profiling of Mycobacterium tuberculosis DosR protein Rv0569 reveals its ability to switch on Th1 based immunity( 2022-02-01) Kanaparthi, Kala Jyothi ; Afroz, Sumbul ; Minhas, Gillipsie ; Moitra, Anurupa ; Khan, Rafiq Ahmad ; Medikonda, Jayashankar ; Naz, Saima ; Cholleti, Sai Nikhith ; Banerjee, Sharmistha ; Khan, NooruddinMycobacterium tuberculosis (M.tb) is a multifaceted bacterial pathogen known to infect more than 2 billion people globally. However, a majority of the individuals ( > 90%) show no overt clinical symptoms of active Tuberculosis (TB) and, it is reported that M.tb in these individuals resides in the latent form. Therefore, a huge burden of latently infected population poses serious threat to the human health. Inconsistent efficacy of BCG vaccine and poor understanding of latency-associated determinants contribute to the failure of combating M.tb. The discovery of DosR as the master regulator of dormancy, opened new avenues to understand the pathophysiology of the bacterium. Though the specific functions of various DosR genes are yet to be discovered, they have been reported as potent T-cell activators and could elicit strong protective immune responses. Rv0569 is a DosR-encoded conserved hypothetical protein overexpressed during dormancy. However, it is not clearly understood how this protein modulates the host immune response. In the present study, we have demonstrated that Rv0569 has a high antigenic index and induces enhanced secretion of Th1 cytokines IL-12p40 and TNF-α as compared to Th2 cytokine IL-10 in macrophages. Mechanistically, Rv0569 induced the transcription of these pro-inflammatory signatures through the activation of NF-κB pathway. Further, immunization of mice with DosR protein Rv0569 switched the immune response towards Th1-biased cytokine pattern, characterized by the enhanced production of IFN-γ, IL-12p40, and TNF-α. Rv0569 augmented the expansion of antigen-specific IFN-γ and IL-2 producing effector CD4+and CD8+ T-cells which are hallmarks of Th1 biased protective immunity. Additionally, IgG2a/IgG1 and IgG2b/IgG1 ratio in the serum of immunized mice further confirmed the ability of Rv0569 to skew Th1 biased immune response. In conclusion, we emphasize that Rv0569 has the ability to generate signals to switch on Th1-dominated responses and further suggest that it could be a potential vaccine candidate against latent M.tb infection.