Conformational activation of GSK3β by an environmental toxicant suppresses hedgehog signalling

Abstract

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.