title: Sent to destroy: the ubiquitin proteasome system regulates cell signaling and protein quality control in cardiovascular development and disease.
abstract: The ubiquitin proteasome system (UPS) plays a crucial role in biological processes integral to the development of the cardiovascular system and cardiovascular diseases. The UPS prototypically recognizes specific protein substrates and places polyubiquitin chains on them for subsequent destruction by the proteasome. This system is in place to degrade not only misfolded and damaged proteins, but is essential also in regulating a host of cell signaling pathways involved in proliferation, adaptation to stress, regulation of cell size, and cell death. During the development of the cardiovascular system, the UPS regulates cell signaling by modifying transcription factors, receptors, and structural proteins. Later, in the event of cardiovascular diseases as diverse as atherosclerosis, cardiac hypertrophy, and ischemia/reperfusion injury, ubiquitin ligases and the proteasome are implicated in protecting and exacerbating clinical outcomes. However, when misfolded and damaged proteins are ubiquitinated by the UPS, their destruction by the proteasome is not always possible because of their aggregated confirmations. Recent studies have discovered how these ubiquitinated misfolded proteins can be destroyed by alternative "specific" mechanisms. The cytosolic receptors p62, NBR, and histone deacetylase 6 recognize aggregated ubiquitinated proteins and target them for autophagy in the process of "selective autophagy." Even the ubiquitination of multiple proteins within whole organelles that drive the more general macro-autophagy may be due, in part, to similar ubiquitin-driven mechanisms. In summary, the crosstalk between the UPS and autophagy highlight the pivotal and diverse roles the UPS plays in maintaining protein quality control and regulating cardiovascular development and disease.
authors.affiliation: Division of Cardiology, McAllister Heart Institute, University of North Carolina at Chapel Hill, 8200 Medical Biomolecular Research Building, Chapel Hill, NC 27599-7126, USA.
authors.forename: Monte S
authors.initials: MS
authors.lastname: Willis
authors.forename: W H Davin
authors.initials: WH
authors.lastname: Townley-Tilson
authors.forename: Eunice Y
authors.initials: EY
authors.lastname: Kang
authors.forename: Jonathon W
authors.initials: JW
authors.lastname: Homeister
authors.forename: Cam
authors.initials: C
authors.lastname: Patterson
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D050197:Atherosclerosis / Q000503:physiopathology; D001808:Blood Vessels / Q000196:embryology; D002318:Cardiovascular Diseases / Q000378:metabolism* / Q000503:physiopathology; D002784:Cholesterol / Q000378:metabolism; D006801:Humans; D008247:Lysosomes / Q000502:physiology; D051379:Mice; D009124:Muscle Proteins / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000502:physiology; D018384:Oxidative Stress; D046988:Proteasome Endopeptidase Complex / Q000502:physiology*; D051381:Rats; D051880:Receptors, Notch / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D025801:Ubiquitin / Q000502:physiology*; D056811:Unfolded Protein Response / Q000502:physiology*; D014657:Vasculitis / Q000503:physiopathology
chemical_list: D009124:Muscle Proteins; D009363:Neoplasm Proteins; D051880:Receptors, Notch; D025801:Ubiquitin; C021081:recognins; D002784:Cholesterol; D046988:Proteasome Endopeptidase Complex