Uncover how the heme-oxidative stress pathway controls protein degradation via the Ubiquitin-Proteasome System

 

Ubiquitin-Proteasome System (UPS)-regulated protein degradation is an irreversible mechanism utilized by numerous biological processes that are modulated through selective elimination of proteins, therefore making the UPS the ultimate on–off switch of a cell. The ubiquitylation process is controlled through an enzymatic cascade in which molecules of ubiquitin are acti­vated by an E1 enzyme, transferred to an E2 ubiquitin-conjugating enzyme and finally transferred to a protein-substrate recognized by an E3 ubiquitin ligase.  In humans, there are only two E1 enzymes, ~30 E2 enzymes, and ~600 E3 enzymes. This remarkable evolutionary feature of the UPS cascade allows the cells to direct the ubiquitylation process with extreme selectivity and specificity. It is estimated that >80% of proteins undergo UPS-mediated degra­dation, therefore the selection of specific substrates by E3 ubiq­uitin ligases in response to specific stimuli plays a central role in the life of the cells.

 

Research from our and other laboratories uncovered that binding of signaling heme to several proteins, such as BACH1 or p53, promotes their UPS-dependent degradation, thus revealing unprecedented roles of signaling heme in regulating protein turnover via the UPS. Interestingly, despite the potential widespread impact of the heme-UPS pathway on the mechanisms controlling cellular homeostasis, heme-dependent protein degradation represents a fundamental and complex scientific question that remains poorly studied. 
To address this question our laboratory leverages a broad spectrum of experimental systems to:

 

1.  Define the heme degradome (i.e., heme-regulated proteome). We seek to identify new heme-UPS substrates and characterize their downstream pathways. We also investigate the molecular machineries regulating the heme degradome, such as E3 ubiquitin ligases and deubiquitylating enzymes, that may work as heme sensors by coupling regulation of protein degradation with variations of the heme signal. 

 

2.  Unravel the mechanisms underlying heme-regulated protein destruction.  Our studies demonstrate a novel regulatory role for heme in promoting the interaction between a ubiquitin ligase (i.e., FBXO22) and its substrates (i.e., BACH1), suggesting that heme may have evolved to allow for regulation of protein stability by modulating the dynamics of “substrate-ubiquitin ligase” interaction. In this context, our team is poised to address the fundamental question: how does heme control protein degradation? To answer this question, we investigate how UPS machineries exploit heme to control protein degradation.