The TBCK-PPP1R21-FERRY3/C12orf4 complex: a RAB5-GAP brake essential for endo-lysosomal homeostasis

TBCK syndrome is a severe neurodevelopmental disorder characterized by hypotonia, intellectual disability, and progressive neurodegeneration. While the TBCK gene has been implicated in MTOR signaling, its primary molecular function has remained controversial. In a recent study, we identify TBCK as the catalytic core of a heterotrimeric complex comprising TBCK, PPP1R21, and FERRY3/C12orf4. This complex functions as a specific GTPase-activating protein (GAP) for RAB5. TBCK deficiency or missense mutations of its key residues in the RABGAP-TBC domain lead to constitutive RAB5 hyperactivation, which blocks the transition from early to late endosomes and results in the formation of massively enlarged RAB5-positive endosomes. Furthermore, this RAB5 hyperactivation drives the constitutive activation of the PIK3C3/VPS34 complex. These defects culminate in a failure of lysosomal enzyme delivery and a secondary collapse of macroautophagic/autophagic flux. These findings redefine TBCK syndrome as a primary disorder of endosomal dynamics and highlight the TBCK-PPP1R21-FERRY3 axis as a critical “brake” for maintaining neuronal homeostasis.