Study of the role of STIP1 and associated factors to the proteostasis network and pluripotency regulation.

Author(s)

Camila Felix de Lima Fernandes

• Document type: Doctoral Thesis
• Press: São Paulo.
• Institution: Universidade de São Paulo (USP). Instituto de Ciências Biomédicas (ICB/SDI)
• Defense date: 2024-04-26

Examining board members

Marilene Hohmuth Lopes; Júlio César Borges; Lygia da Veiga Pereira Carramaschi; Enrique Mario Boccardo Pierulivo

• Advisor: Marilene Hohmuth Lopes

Abstract

Stress-inducible phosphoprotein 1 (STIP1) is an evolutionarily conserved protein formed by three repetitive tetratricopeptide domains and two dipeptide domains rich in aspartate and proline residues. The structure of STIP1 is closely associated with its multifunctionality in cells, being found in the cytoplasm, nucleus, and extracellular environment. One of the main functions of STIP1 is its role as a co-chaperone, allowing the formation of a protein complex between the heat shock proteins HSP70 and HSP90, assisting in the folding and processing of several other proteins, named clients of this molecular machinery. The complex formed by STIP1 is essential for the maintenance of protein homeostasis, or proteostasis. Total depletion of STIP1 in mice leads to embryo degeneration, but despite the elucidated phenotype, the exact molecular mechanisms that lead to early collapse in these animals are unknown. Mouse embryonic stem cells (mESCs) represent one of the most efficient in vitro models to mimic early mammalian embryonic development. ESCs are classified as pluripotent stem cells (PSCs), as they can differentiate into any adult somatic phenotype under appropriate stimuli and can self-renew indefinitely without cellular senescence. PSCs have advanced proteome control mechanisms, including increased synthesis of chaperones and co-chaperones, such as STIP1. Many crucial factors in the biology of PSCs remain unknown. Therefore, understanding the molecular bases associated with the maintenance of pluripotency is of fundamental importance, both for the use of these cells in scientific research and the release of their therapeutic potential. Thus, 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. Furthermore, we seek to find new molecular pathways, possibly modulated by STIP1, associated with the control of pluripotency and early development of mammals. (AU)

• FAPESP's process: 19/14741-9 - Study of the role of STI1 and assotiated factors in the proteostasis network and pluripotency regulation
• Grantee: Camila Felix de Lima Fernandes
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)