SEC14L2 couples chaperone-mediated autophagy to microtubule stability by targeting Stathmin 1

Microtubule dynamic instability underpins cellular architecture, division, and intracellular trafficking, yet how selective proteolytic pathways tune core microtubule regulators remains incompletely understood. Here, we identify SEC14L2 (SEC14-like lipid binding 2), a multidomain lipid transfer protein, as a determinant of microtubule organization and cellular architecture by limiting the accumulation of the microtubule-destabilizing factor Stathmin 1 (STMN1). We further show that STMN1 is a substrate of chaperone-mediated autophagy (CMA) and that SEC14L2 is required for efficient CMA-dependent STMN1 turnover. SEC14L2 loss is associated with reduced CMA activity, STMN1 stabilization, collapse of the microtubule network, and perinuclear organelle clustering. In breast cancer cell models, perturbation of this SEC14L2-CMA-STMN1 axis alters responses to microtubule-targeting agents. This study shows SEC14L2 maintains cell architecture by promoting the autophagy-mediated degradation of STMN1. This pathway regulates microtubule organization and modulates chemotherapy responses in breast cancer cells.