Biology subjects

Bhattacharjya, A.

Publications and source records attributed to Bhattacharjya, A..

3 recordsLinked to original sources

bioRxiv2026

Conformational activation of GSK3β by an environmental toxicant suppresses hedgehog signalling

Primary cilium-dependent hedgehog signalling is essential for embryonic development, tissue patterning, and organ homeostasis, and its dysfunction causes ciliopathies, a clinically diverse spectrum of developmental and reproductive disorders. Whether environmental chemicals can phenocopy genetic ciliopathies by directly targeting ciliary kinase machinery has remained unknown. Here we show that endosulfan, a banned organochlorine pesticide linked to congenital and reproductive defects, suppresses hedgehog signalling by driving proteolytic processing of GLI transcription factors into repressor forms. Excluding ciliary receptor trafficking, cAMP signalling, and GLI-DNA binding, we identify PKA and GSK3{beta} as direct endosulfan targets: endosulfan allosterically fine-tunes PKA activity and, to our knowledge, is the first reported small-molecule activator of GSK3{beta}, stabilising its active conformation, a profile distinct from all known inhibitors. We further identify Cetn3 and Cep250 as novel GLI-regulated genes required for centriole cohesion, both of which are repressed upon endosulfan exposure, linking this kinase axis to the reproductive defects reported in exposed human populations and animal models. These findings establish a chemical-biological axis through which an environmental toxicant hijacks core kinase signalling to phenocopy a genetic ciliopathy.

cell biology↗

bioRxiv2026

Endosulfan rewires PKA and GSK3β to disrupt primary cilia-dependent Hedgehog signalling

Primary cilium-dependent Hedgehog signalling is essential for embryonic development, tissue patterning, and organ homeostasis, and its disruption causes a spectrum of developmental disorders collectively termed ciliopathies. Whether environmental toxicants can chemically induce ciliopathy-like states by targeting this pathway, however, remains poorly understood. Here we show that endosulfan, a banned organochlorine pesticide epidemiologically linked to severe congenital and reproductive defects in exposed human populations, disrupts Hedgehog signalling by driving GLI transcription factor processing into repressor forms and suppressing target gene expression at both transcriptional and protein levels. Having excluded direct effects on core ciliary receptors and GLI-DNA binding, we identify the pathway kinases PKA and GSK3{beta} as direct targets of endosulfan: endosulfan increases PKA activity through allosteric fine-tuning, and -- in a pharmacologically rare finding -- acts as the first reported small-molecule activator of GSK3{beta}, shifting the kinase toward a catalytically active conformation. We further identify Cetn3 and Cep250 as novel GLI-regulated genes required for centriole cohesion, both of which are repressed upon endosulfan exposure, providing a mechanistic link to the reproductive defects reported in exposed populations and animal models. These findings identify endosulfan as a candidate chemical inducer of ciliopathy and reveal how an environmental toxicant can hijack core kinase signalling to disrupt Hedgehog-dependent development.

cell biology↗

bioRxiv2022

Denaturation resistant P2 tetramer imports fatty acids from human serum into intraerythrocytic Plasmodium falciparum

The initiation of asymmetric karyokinesis of intraerythrocytic Plasmodium falciparum (Pf) begins without dismantling the nuclear envelope showing the hallmark feature of closed mitosis (1-10). In Pf, karyokinesis precedes cytokinesis and cell body formation (6, 8-10). Regulation at the beginning of nuclear division either through checkpoints or by importing serum components was largely unknown. At the trophozoite stage, PfP2 tetramer trafficked to the infected erythrocyte (IE) surface and the inaccessibility of IE surface PfP2 to its bonafide ligand led to the arrest of nuclear division (11-13). Here we show that PfP2 tetramer localization on the IE surface and the beginning of nuclear division are concomitant in nature. Synthetically induced denaturation resistant PfP2 tetramer interacts with human serum fatty acids and phospholipids for its import into IEs at the beginning of karyokinesis. In the natively folded denaturation resistant PfP2 tetramer cage, the Cys-Cys redox switch regulates the binding and subsequent release of fatty acids on the IE surface. This mechanistic insight of fatty acids import inside IEs using synthetically induced denaturation resistant PfP2 tetramer provides an unique drug screening platform for novel small molecule screening against malaria.

molecular biology↗