The role of microtubule acetylation in SASP modulation (360G-Wellcome-300516_Z_23_Z)

Cellular senescence is a state of permanent cell cycle arrest that occurs in response to unresolved cellular stress. Acute induction of senescence is beneficial for tissue physiology, as it prevents replication of old or pre- malignant cells. However, lingering senescent cells drive a variety of age- related pathologies through secretion of a complex mixture of paracrine factors, known as the Senescence Associated Secretory Phenotype (SASP). Therefore, approaches that specifically inhibit or alter the SASP could have broad implications for the development of therapeutic strategies. However, this requires extensive knowledge of the mechanisms that drive secretion in senescent cells, which currently remain elusive. My preliminary data point towards an important role for microtubules in regulating the SASP, involving tubulin posttranslational modifications (PTMs) that could affect microtubule- based transport of secretory vesicles. This work provides the first evidence that microtubule alterations directly regulate secretion in a relevant physiological context. This proposal will: (1) identify the mechanisms that control microtubule PTMs in senescent cells, (2) investigate how tubulin PTMs affect secretion of SASP factors using advanced proteomics approaches, combined with orthogonal strategies to modulate tubulin PTMs, and (3) determine how microtubule PTMs affect non-cell autonomous SASP signalling using established in vitro and in vivo model systems.