The role of TonEBP on the regulation of microtubule dynamics and ciliogenesis.

Abstract

ABSTRACT

Microtubules are fundamental components of the cytoskeleton essential for maintaining cellular architecture, facilitating intracellular transport, and enabling cell division. Additionally, microtubules are the core structural components of primary cilia, which are slender, microtubule-based organelles that extend from the cell surface. Primary cilia act as essential sensory antennae, detecting and transducing extracellular signals that regulate a myriad of cellular processes, including development, differentiation, and tissue homeostasis. TonEBP is a transcription factor canonically associated with cellular response to hypertonic stress, during which microtubule cytoskeleton and primary cilia play contributing roles to this adaptation. However, a direct link among TonEBP, microtubule cytoskeleton and primary cilia is unclear. This study introduces a novel role of TonEBP as a regulator of microtubule dynamics and ciliogenesis. Initial findings reveal that TonEBP is enriched at the centrosome – the main microtubule organizing center. Interestingly, the stability of TonEBP is dependent on intact microtubule network, disruption of which causes rapid degradation of TonEBP. This has shown to be necessary for efficient microtubule regrowth, as presence of TonEBP inhibits microtubule nucleation at the centrosome. Moreover, TonEBP is a negative regulator of ciliogenesis. Depletion of TonEBP facilitates the formation of primary cilia, whereas its overexpression results in fewer ciliated cells. Furthermore, TonEBP modulates the expression and activity of aurora kinase A, a key negative regulator of ciliogenesis. Finally, TonEBP regulates the integrity of centriolar satellites, which are essential for primary cilia formation. Collectively, this dissertation proposes previously uncharacterized regulation of TonEBP on microtubule dynamics and ciliogenesis, revealing a novel physiological function of TonEBP.