Progetto Prin 2015
The ubiquitin pathway regulates many biological processes and determines how cells respond to growth factors, stress and genetic damage, controlling nearly every facet of a cell's life and death. E3 ligases are the master players of the ubiquitination process. During the past two decades evidence has accumulated, supporting a paramount role of these proteins in the regulation of various biological and pathological phenomena. A detailed understanding of the role exerted by these enzymes as well as the identification and characterization of their substrates and regulators is critical in developing new approaches for therapies. The main aim of this project is to provide new insights on how cells exploit E3 ubiquitin ligases to sense cellular stresses and to activate survival processes in a selective and timely manner. We propose to perform an in-depth investigation on how ubiquitination decoys stress signals to target damaged organelles for degradation and to dynamically adapt the activities of cellular structures. We will focus on autophagy, a survival process that allows the prompt removal of injured cell components and prevents cell death unless damage results irreversible. This choice is motivated by three main reasons: 1) autophagy is considered the first response activated by virtually any kind of intracellular and extracellular stress; 2) ubiquitination is known to play a role in many steps of autophagy regulation; 3) selective forms of autophagy are often activated by ubiquitination events, suggesting high specificity in terms of E3 ligases implicated in a particular stress response. How stress response is regulated by E3 ligases will be investigated in four different processes in which these proteins play crucial roles: DNA damage, oxidative stress, primary cilium sensing, and bacterial infection. In these systems, we will investigate, by multiple methodological approaches, the ability of E3 ubiquitin ligases to activate response pathways to respond to stress and prevent that resulting damages will endanger the integrity of the entire cell. If successful, our work will lead to i) the elucidation of autophagy substrates/interactors of TRIM18, TRIM32, HECW1, and CSA; ii) the characterization of the mechanism of action of the above-mentioned E3 ligases and the UBL-containing protein HOPS in selective autophagy; and iii) the definition of the role exerted by this set of proteins in diverse human diseases. It is anticipated that the studies addressed in this proposal will have broad biological impact and would potentially lead to clinical and therapeutic implications, including the identification of novel pharmacological targets.
Ubiquitin E3 ligases as critical sensors in physiological and pathological conditions
PASCUCCI Barbara
2016
Abstract
The ubiquitin pathway regulates many biological processes and determines how cells respond to growth factors, stress and genetic damage, controlling nearly every facet of a cell's life and death. E3 ligases are the master players of the ubiquitination process. During the past two decades evidence has accumulated, supporting a paramount role of these proteins in the regulation of various biological and pathological phenomena. A detailed understanding of the role exerted by these enzymes as well as the identification and characterization of their substrates and regulators is critical in developing new approaches for therapies. The main aim of this project is to provide new insights on how cells exploit E3 ubiquitin ligases to sense cellular stresses and to activate survival processes in a selective and timely manner. We propose to perform an in-depth investigation on how ubiquitination decoys stress signals to target damaged organelles for degradation and to dynamically adapt the activities of cellular structures. We will focus on autophagy, a survival process that allows the prompt removal of injured cell components and prevents cell death unless damage results irreversible. This choice is motivated by three main reasons: 1) autophagy is considered the first response activated by virtually any kind of intracellular and extracellular stress; 2) ubiquitination is known to play a role in many steps of autophagy regulation; 3) selective forms of autophagy are often activated by ubiquitination events, suggesting high specificity in terms of E3 ligases implicated in a particular stress response. How stress response is regulated by E3 ligases will be investigated in four different processes in which these proteins play crucial roles: DNA damage, oxidative stress, primary cilium sensing, and bacterial infection. In these systems, we will investigate, by multiple methodological approaches, the ability of E3 ubiquitin ligases to activate response pathways to respond to stress and prevent that resulting damages will endanger the integrity of the entire cell. If successful, our work will lead to i) the elucidation of autophagy substrates/interactors of TRIM18, TRIM32, HECW1, and CSA; ii) the characterization of the mechanism of action of the above-mentioned E3 ligases and the UBL-containing protein HOPS in selective autophagy; and iii) the definition of the role exerted by this set of proteins in diverse human diseases. It is anticipated that the studies addressed in this proposal will have broad biological impact and would potentially lead to clinical and therapeutic implications, including the identification of novel pharmacological targets.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
