A newly published study from researchers at UMass Chan Medical School unveils a critical molecular mechanism underlying severe human ciliopathies, a group of devastating genetic disorders linked to defects in cellular antennae known as cilia. In groundbreaking research led by Dr. Sumeda Nandadasa and colleagues, scientists have precisely mapped how the TMEM67 protein—implicated in Meckel-Gruber syndrome, nephronophthisis, and Joubert syndrome—is enzymatically cleaved to produce two functionally distinct isoforms. This dual-function cleavage not only offers deep insights into cilia biogenesis but also untangles its role in vital intracellular signaling pathways, offering promising new avenues for therapeutic development.
Cilia, microtubule-based organelles extending from nearly all mammalian cells, perform an array of essential roles ranging from motility and sensory functions to the transduction of biochemical signals. Malfunction or structural aberrations in cilia culminate in ciliopathies, a heterogeneous group of multisystemic disorders. Patients with mutations in the TMEM67 gene often suffer from the most severe ciliopathies, including Meckel-Gruber syndrome, characterized by embryonic lethality and profound developmental anomalies. Until now, the mechanistic details of TMEM67’s involvement in these pathologies remained obscure.
The UMass Chan team discovered that TMEM67 is not a monolithic protein entity; rather, it undergoes a highly specific proteolytic cleavage by the enzyme ADAMTS9 at an evolutionarily conserved site. This cleavage event results in two isoforms with separate and indispensable functions. The first isoform localizes to the ciliary transition zone, a strategically important gating region positioned at the base of the cilium. This gate functions as a molecular checkpoint that regulates the trafficking of proteins and lipids, effectively maintaining the biochemical compartmentalization of the ciliary compartment which is critical for cilia stability and signaling.
Failure to execute the cleavage of TMEM67 leads to the retention of a noncleaved isoform that disrupts cilia gating mechanisms. In such mutated scenarios, cilia frequently exhibit dysmorphic appearances such as abnormal ballooning or satellite-dish-like expansions, reflecting defective structural integrity and impaired signaling capacity. This dysfunction is a hallmark of syndromic ciliopathies, wherein compromised ciliary dynamics translate to broad developmental and physiological defects observable in patients.
In parallel, the uncut TMEM67 isoform plays a pivotal role in facilitating noncanonical Wnt signaling. The Wnt signaling pathway is a highly conserved cellular communication system that regulates numerous developmental processes, including cell proliferation, differentiation, and polarity. The study reveals that the noncleaved TMEM67 isoform acts as a critical transducer within this pathway, emphasizing TMEM67’s dual-functionality—balancing structural roles in ciliogenesis and molecular control in cell signaling.
Employing state-of-the-art proteomics and mass spectrometry technologies, the researchers pinpointed the exact cleavage site conserved across diverse species including murine models, the nematode Caenorhabditis elegans, and humans. This interspecies conservation underscores the fundamental evolutionary importance of TMEM67’s cleavage and its associated bifunctional roles. Such evolutionary preservation suggests that perturbations in this cleavage mechanism have dire developmental consequences that have been negatively selected throughout evolution.
This research also highlights the broader biological principle of protein multifunctionality through regulated proteolysis. By generating isoforms with distinct cellular destinations and functions, cells achieve regulatory complexity and precision indispensable for organismal development and homeostasis. Specifically, the duality of TMEM67 allows it to act simultaneously as a structural scaffold at the cilium base and as a signaling mediator within the Wnt pathways.
The clinical implications of these findings are profound. Ciliopathies represent a challenging class of diseases for which no targeted therapies currently exist. Understanding the dual roles of TMEM67 and the molecular nuances of its cleavage provides a concrete molecular target. Future drug discovery efforts may focus on modulating TMEM67 cleavage or mimicking the function of its isoforms to restore normal ciliary function and cell signaling in affected patients.
The interdisciplinary collaboration among developmental biologists, geneticists, and cell biologists at UMass Chan Medical School further underscores the power of integrating proteomics, genetics, and model organism research to dissect complex biological questions. Postdoctoral fellow Manu Ahmed and PhD candidate Sydney Fischer were instrumental contributors to expanding the mechanistic framework of this investigation.
Moreover, the study advances knowledge on the interplay between ciliary biology and signal transduction pathways. Cilia have long been appreciated for their sensory roles, but this research emphasizes how their assembly and signaling capacities are finely coordinated through post-translational processing of critical proteins like TMEM67. The insights extend beyond ciliopathies, potentially informing the pathophysiology of other disorders involving Wnt signaling and cellular compartmentalization.
Looking forward, the team plans to dissect the independent mechanisms by which each TMEM67 isoform exerts its effects and to explore potential compensatory pathways that may be recruited when normal cleavage is disrupted. These endeavors will pave the way for novel intervention strategies aimed at mitigating the severe developmental defects associated with TMEM67 mutations.
This landmark study published in Nature Communications not only elucidates a fundamental biological process but also brings hope to families affected by ciliopathies. It exemplifies how detailed molecular dissections can unravel disease mechanisms and guide the development of next-generation therapeutics in rare genetic disorders with devastating clinical outcomes.
Subject of Research: Animals
Article Title: Cleavage of the Meckel-Gruber syndrome protein TMEM67 by ADAMTS9 uncouples Wnt signaling and ciliogenesis
News Publication Date: 28-May-2025
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Image Credits: Photo by Bryan Goodchild, UMass Chan Medical School
Keywords:
Cilia, Primary cilia, Cell biology, Genetic disorders
