Primary cilia are antenna-like sensory organelles that are essential for signalling pathways and homeostasis. At the ciliary base, the transition zone (TZ) acts as a diffusion barrier, regulating the selective entry and exit of ciliary proteins. The TZ is organised by distinct protein modules, including the Meckel syndrome (MKS) module, whose disruption is associated with ciliopathies. Mutations in TXNDC15 (MKS14), a thioredoxin (TRX) protein associated with protein folding in the endoplasmic reticulum (ER) and essential for TZ integrity, have been identified in individuals with MKS. Here (Yamazaki et al., 2024), Yohei Katoh and colleagues show that TXNDC15 regulates the integrity of the TZ from the ER. The authors generate TXNDC15-knockout (KO) retinal pigment epithelial cells and confirm via immunofluorescence that TXNDC15 loss disrupts the TZ assembly of the MKS module. Moreover, exogenously expressed TXNDC15 and its MKS-associated variants predominantly localise to the ER, but not cilia, suggesting an indirect role in TZ regulation. Finally, the N-terminal TRX domain is crucial for rescuing ciliary protein localisation. Taken together, these findings suggest that TXNDC15 supports MKS module assembly in the cilia, possibly by mediating the folding of TZ proteins in the ER, offering new insights into ciliary dysfunction in human disease.
