TRIM10β upregulation promotes microtubule destabilization and triggers proteotoxic stress.

Abstract

Microtubule stability is critical for maintaining cytoskeletal integrity and is finely tuned by post-translational modifications of tubulin and its associated regulatory factors. However, it remains unclear how microtubules become destabilized under stress or disease conditions and contribute to pathogenesis. Here, we identify TRIM10β, a previously uncharacterized splice variant of TRIM10, as a microtubule-associated protein that disrupts the interaction between tubulin and End Binding protein 1 (EB1), which plays a critical role in microtubule stabilization. Moreover, TRIM10β promotes tubulin SUMOylation and cleavage of LIM domain kinase 1 (LIMK1), both of which contribute to microtubule destabilization. TRIM10β binds to calmodulin-regulated spectrin-associated protein 2 (CAMSAP2), a key regulator of non-centrosomal microtubules, and modulates its protein levels via its E3 ligase activity. Notably, TRIM10β depletion attenuates p38 phosphorylation in erythroblasts, which is essential for microtubule disassembly and polarization during enucleation, whereas its ectopic expression aberrantly enhances p38 activity, promoting microtubule disassembly in non-erythroid cells. Importantly, persistent overexpression of TRIM10β is recognized as a proteotoxic burden and rapidly degraded via the unfolded protein response (UPR) under cellular stress, thereby serving as a protective mechanism. Our findings reveal a novel role for TRIM10β in microtubule dynamics and highlight a potential regulatory mechanism in maintaining proteostasis, with its low endogenous expression possibly reflecting an evolutionary strategy to minimize proteostatic stress.