Biology subjects

Sarmadhikari, D.

Publications and source records attributed to Sarmadhikari, D..

3 recordsLinked to original sources

bioRxiv2026

Bisphenol-A mediated ubiquitinome alteration triggers PPAR-alpha ubiquitination, affecting trophoblast cell migration

Pregnant women are frequently exposed to various endocrine-disrupting chemicals (EDCs), such as bisphenol A (BPA), causing harm to both the developing placenta and fetus. BPA can promote placental dysfunction by altering key cellular processes such as differentiation, invasion, and migration in trophoblast cells. These cellular processes are also tightly managed by the ubiquitin proteasomal system via maintenance of the ubiquitinated protein pool. However, the BPA-mediated dysregulation of this ubiquitin proteasomal homeostasis is poorly understood. Therefore, we identified 19 deubiquitinases (DUBs) and a dynamic ubiquitinome profile of extravillous trophoblast cells (HTR8/SVneo), which reduced trophoblast cell migration post-BPA exposure. Further investigation using an integrated substrate-ligase-deubiquitinase network shows that BPA binding to PPAR-alpha or indirect regulation of its E3 Ligase MuRF1 and DUB USP5 via BPA resulted in hyper-ubiquitination of PPAR-alpha, triggering its nuclear localization. In the nucleus, the ubiquitinated PPAR-alpha can deregulate its migration-associated target gene expression, causing a reduction in the migration of HTR8/SVneo cells. This physiological alteration of extravillous trophoblast cells (EVTs) through BPA can disrupt placental homeostasis. Hence, we assumed that BPA-induced cellular alteration in EVTs can promote placental defects, which might contribute to adverse pregnancy outcomes.

biochemistry↗

bioRxiv2025

Cholesterol-mediated activation of VapC12 toxin modulates growth and drug susceptibility in Mycobacterium tuberculosis

Tuberculosis eradication efforts are severely hampered by antimicrobial resistance (AMR). We have previously reported that VapBC12 TA system in Mycobacterium tuberculosis (M. tuberculosis) regulates both disease and antibiotic persistence in tuberculosis. In this study, we developed a mechanistic understanding of the VapBC12-dependent modulation of growth and antibiotic susceptibility in M. tuberculosis. We identified a unique Cholesterol Recognition Amino acid Consensus (CRAC) motif in VapC12 toxin and demonstrated that its heterologous expression induces toxicity in M. smegmatis. We have solved the crystal structure of VapB12 antitoxin at a 1.6A0 wavelength and using molecular modeling predicted the structure of TA complex. Structure-function analysis revealed specific residues critical for the assembly and activity of the VapBC12 TA system. Our study suggests that cholesterol activates the VapC12 toxin by competitively displacing its cognate antitoxin at the CRAC motif which consequently restricts the growth of M. tuberculosis. Finally, we demonstrated that chemical inhibition of VapC12 prevents growth restriction and potentiates activity of anti-TB drugs.

microbiology↗

bioRxiv2025

AGPAT1 is a novel Chikungunya virus receptor on human cells

Chikungunya virus (CHIKV) is a medically important alphavirus whose host receptor is not fully understood. We identified AGPAT1 from the human Huh7 cell plasma membrane binding with CHIKV particles in vitro. The CHIKV binding with AGPAT1 was demonstrated on Huh7, HAP1, and ERMS plasma membrane by confocal microscopy. The AGPAT1 antibody inhibited CHIKV binding to cells, reducing the virus uptake in Huh7 and ERMS cells. CHIKV binding, uptake, and replication were significantly reduced in the AGPAT1 knockout HAP1 cells, and the ectopic expression of AGPAT1 rescued the reduced virus binding, uptake, and replication. AGPAT1 interacted with the E1 surface on the E1-E2 dimer of CHIKV envelope proteins in silico. The E1-AGPAT1 interacting amino acid residues identified in the computational study were experimentally verified. AGPAT1 was also shown to have a role in the binding and uptake of another alphavirus, Ross River virus. These data demonstrate an important role for AGPAT1 as a novel host receptor involved in CHIKV binding and uptake in human cells. AUTHOR SUMMARYChikungunya virus (CHIKV) is a medically important alphavirus. Identifying its receptor on human cells will aid the development of novel antivirals. We have identified AGPAT1 as a novel CHIKV receptor on several human cells. We provide data showing the interaction of AGPAT1 with the E1 protein of CHIKV E1-E2 dimer present on the virion surface and identify the amino acid residues involved in the interaction. AGPAT1 was also shown to have a role in the binding and uptake of Ross River virus, another alphavirus. AGPAT1 is a protein involved in lipid metabolism and has not been reported to have a direct role in any virus infection, or as a virus receptor. Thus, this work identifies AGPAT1 as a novel receptor for CHIKV on human cells, and has implications for understanding the virus pathogenesis and designing the receptor-blocking CHIKV antivirals.

microbiology↗