Study of the role of STI1 and assotiated factors in the proteostasis network and pluripotency regulation

Abstract

Stress Inducible Protein 1 (STI1) corresponds to an evolutionary conserved protein, formed by three repetitive tetratricopeptides domains, and two additional domains rich in aspartate and proline. The structure of STI1 is closely associated with its multifunctionality in cells, being found in the cytoplasm, nucleus and extracellular environment. One of the main functions of STI1 is its role as a cochaperone, allowing the formation of a protein complex between HSP70-HSP90 heat shock proteins, aiding in the folding and processing of several other proteins, client of this molecular machinery. The complex formed by STI1 is essential for the maintenance of protein homeostasis (proteostase). Total depletion of STI1 in mice leads to embryo unviability, but despite the elucidated phenotype, the exact molecular mechanisms leading to the early degeneration of these animals are not fully known. Mouse Embryonic Stem Cells (mESCs) represent one of the most efficient in vitro models to mimic the early embryonic development of mammals. ESCs are classified as Pluripotent Stem Cells (PSCs), as they have the ability to differentiate into any adult somatic phenotype under proper stimuli, and can self-renew indefinitely without cellular senescence. PSCs have advanced proteome control mechanisms, including increased synthesis of chaperones and cochaperones, such as STI1. Many crucial factors in the biology of PSCs remain unknown, and therefore understanding the molecular basis associated with the maintenance of pluripotency is of fundamental importance, both for the use of these cells in research of degenerative diseases and aging, as well as the release of their therapeutic potential. Therefore, the present project aims to shed light on aspects associated with the control of PSCs and their potential for differentiation, proliferation and self-renewal through proteostasis mechanisms. Also, we seek to find new molecular pathways, possibly modulated by STI1, associated to the control of pluripotency and initial development of mammals. (AU)