Managing the Quality of Life for Proteins: Focusing on the Exit Path

This special issue of Molecular Cellular Proteomics is dedicated to highlight outstanding scientific advances reported at the 2010 Proteomics of Protein Degradation and Ubiquitin Pathways (PPDUP) meeting in Vancouver, British Columbia, Canada. This conference was jointly sponsored by the International Forum of Proteomics and Proteomics of Protein Degradation and Ubiquitin Pathways, and it is the first of a series of conferences on the related topic. The major goal of this series of conferences is to promote the elucidation of protein degradation pathways and the understanding of downstream physiologic consequences using cutting-edge proteomic tools. The main biological questions revolve around how cells manage their protein quality of life and how proteins are processed when they reach the end of their road. Scientific content covered by this international conference spanned a wide range of topics all converging on protein misfolding, protein quality control, and all relevant protein degradation pathways, which have been extensively reviewed by Drs. Peter Kaiser (University of California, Irvine (UCI)) and Thibault Mayor (University of British Columbia (UBC)) in this special issue. A number of complex diseases, including cardiovascular diseases, neuronal disorders, cystic fibrosis, and muscular dystrophy, have been linked to malfunctions in protein degradation pathways. These disease phenotypes are complex, and it has remained a major challenge to both the scientists as well as the clinicians to define their etiologies as well as their underlying pathogeneses. Despite limited understanding on the cause and trigger of these diseases, progress has been made; there is increasing recognition that they are caused by convoluted, multipathway perturbations, rather than the disruption of any single molecular event. Accordingly, proteomic technologies are uniquely suited for the advancement of our knowledge in the protein degradation field and for the translation of these findings to clinical application by offering global analysis capabilities. Unbiased and comprehensive proteomic characterization of degradation pathways will lead to the identification of novel molecular networks, and will discover points of signaling convergence to be exploited for therapeutic intervention. To address these emerging challenges in the field, this special issue of Molecular and Cellular Proteomics (MCP) has compiled seminal contributions from leaders in the protein degradation field. The laboratory of Dr. Lan Huang (UC Irvine) extensively reviewed oxidative stress-mediated alterations in the dynamics of proteasome complexes and their biological roles in modulating the downstream accumulation of cytotoxic protein aggregates that are prominent in neurodegenerative diseases. Dr. Daniel Finley (Harvard) and colleagues reviewed the biological importance of deubiquitinase (DUB) activities acting distal to the substrate in antagonizing substrate degradation by the proteasome. These findings have promising therapeutic implications, in that pharmacological inhibition of specific deubiquitinases may enhance proteasome-dependent protein degradation by boosting substrate entrance dynamics. The group led by Dr. Ugo Mayor (CIC Biogune) reported a novel in vivo ubiquitin biotinylation strategy to isolate ubiquitin conjugates from Drosophila melanogaster neurons. Importantly, these studies led to the discovery of 48 neuronal ubiquitin substrates, many of which were key players in synaptogenesis. The laboratory of Dr. Donald S. Kirkpatrick (Genentech, Inc.) advanced the technological capabilities for mass specrometry-based quantification of diverse and endogenous ubiquitin signals. This study notably highlighted the extreme complexity of ubiquitin signals in the cellular proteome, as evidenced by the finding that polyubiquitinated substrates can be simultaneously modified by a mixture of ubiquitin linkages (K48, K63, and K11). Dr. Christopher M. Overall (University of British Columbia) and colleagues developed a novel liquid chromatograpy (LC)-MS based approach Amino-Terminal Oriented Mass spectrometry of Substrates (ATOMS) for honing in on the amino termini of substrates, which upon cleavage produce bioactive products. ATOMS remarkably identified 55 neutrophil elastase and 34 matrix metalloproteinase cleavage sites in laminin-1 and fibronectin-1, thus demonstrating the importance of this technology in identifying new extracellular protein cleavage products critical in pathology. Dr. Matthew Bogyo (Stanford) and colleagues established the first comprehensive map of the proteolytic events occurring over the time course of the human malarial parasite, Plasmodium falciparum-mediated rupture of host red blood cells during malaria infection. The group led by Dr. Raymond J. Deshaies (California Institute of Technology) unveiled novel signaling mechanisms regarding the SCF (Skp1 adaptor; Cul1 scaffold; F-box substrate recognition subunit) ubiquitin ligase complex. Using quantitative mass spectrometry-based approaches, they demonstrated that inhibiting Nedd8 conjugation led to an unexpected increase in SCF complexes, suggesting that Nedd8 conjugation is not necessary to maintain the steady-state level of SCF ubiquitin ligases. Dr. Jun Qin (Baylor) and colleagues developed an affinity-based technology for the large-scale isolation of polyubiquitinated proteins in mammalian cells, which allowed the successful identification of 294 endogenous ubiquitination sites from human 293T cells. In a second contribution, Dr. Qin reviewed the status of global ubiquitin profiling studies in complex biological systems, and highlighted the central role of unbiased proteomic technologies in propelling the field forward. The group of Michael H. Glickman (Technion, Israel Institute of Technology) elucidated the site-specificity of total cellular ubiquitin conjugates using a rapid lysis technique, which showed that approximately half of conjugated ubiquitin was nonextended. Incorporation of lysine-void ubiquitin demonstrated that despite the utilization of a common ubiquitin molecule, the two major functional branches of ubiquitination machinery, degradation and trafficking, were disproportionately affected by this perturbation. In a second contribution, his group reviewed the activation mechanism and biological roles of the proteasome activator, PA200 (yeast ortholog as Blm10). Crystallographic analysis of the PA200–20S structure has defined the detailed interaction coordinates of these two complexes, which support a critical role for PA200 in stabilizing a partially open conformation of 20S. Dr. Peipei Ping (UCLA) and colleagues described the first isolation and detailed biochemical characterization of functionally viable cardiac 19S complexes. Importantly, cardiac 19S complexes were found to be heterogeneous, with subpopulation I specifically exhibiting sensitivity to Hsp90 inhibition. Identifying unique molecular features of 19S subpopulations opened up new avenues for tailoring proteasome-targeted therapeutic interventions in cardiovascular diseases. Collectively, these studies indicate that the field of protein degradation is being propelled forward via the application and new development of proteomic technologies, which offer unprecedented strategies for answering global questions. These reports in this special issue make evident that this field has moved beyond the single molecular pathway perspective, and has embraced an integrated systems view of biological processes decoding the manner by which proteins are being processed to exit their life. The biological insights offered herein have begun to unveil the functional lesions within these pathways and the potential roles they contribute to the pathogenesis of diseases. We look forward to the success of our next conference addressing “Protein Degradation Pathways in Health and Diseases.”

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