Vulnerability of newly synthesized proteins to proteostasis stress.

Xu, Guilian; Pattamatta, Amrutha; Hildago, Ryan; Pace, Michael C; Brown, Hilda; Borchelt, David R

Xu, Guilian; Pattamatta, Amrutha; Hildago, Ryan; Pace, Michael C; Brown, Hilda; Borchelt, David R.

Afiliación

Xu G; Department of Neuroscience, SantaFe HealthCare Alzheimer's Disease Research Center, Center for Translational Research in Neurodegenerative Disease, McKnight Brain Institute, University of Florida, Gainesville, FL 32610, USA.
Pattamatta A; Interdisciplinary Graduate Program, University of Florida, Gainesville, FL 32610, USA.
Hildago R; College of Arts and Sciences, University of Florida, Gainesville, FL 32610, USA.
Pace MC; Interdisciplinary Graduate Program, University of Florida, Gainesville, FL 32610, USA.
Brown H; Department of Neuroscience, SantaFe HealthCare Alzheimer's Disease Research Center, Center for Translational Research in Neurodegenerative Disease, McKnight Brain Institute, University of Florida, Gainesville, FL 32610, USA.
Borchelt DR; Department of Neuroscience, SantaFe HealthCare Alzheimer's Disease Research Center, Center for Translational Research in Neurodegenerative Disease, McKnight Brain Institute, University of Florida, Gainesville, FL 32610, USA drb1@ufl.edu.

J Cell Sci ; 129(9): 1892-901, 2016 05 01.

Article en En | MEDLINE | ID: mdl-27026526

RESUMEN

The capacity of the cell to produce, fold and degrade proteins relies on components of the proteostasis network. Multiple types of insults can impose a burden on this network, causing protein misfolding. Using thermal stress, a classic example of acute proteostatic stress, we demonstrate that â¼5-10% of the soluble cytosolic and nuclear proteome in human HEK293 cells is vulnerable to misfolding when proteostatic function is overwhelmed. Inhibiting new protein synthesis for 30âmin prior to heat-shock dramatically reduced the amount of heat-stress induced polyubiquitylation, and reduced the misfolding of proteins identified as vulnerable to thermal stress. Following prior studies in C. elegans in which mutant huntingtin (Q103) expression was shown to cause the secondary misfolding of cytosolic proteins, we also demonstrate that mutant huntingtin causes similar 'secondary' misfolding in human cells. Similar to thermal stress, inhibiting new protein synthesis reduced the impact of mutant huntingtin on proteostatic function. These findings suggest that newly made proteins are vulnerable to misfolding when proteostasis is disrupted by insults such as thermal stress and mutant protein aggregation.

Asunto(s)

Proteínas de Caenorhabditis elegans/metabolismo; Caenorhabditis elegans/metabolismo; Proteína Huntingtina/metabolismo; Mutación Missense; Biosíntesis de Proteínas; Deficiencias en la Proteostasis/metabolismo; Sustitución de Aminoácidos; Animales; Caenorhabditis elegans/genética; Proteínas de Caenorhabditis elegans/genética; Células HEK293; Humanos; Proteína Huntingtina/genética; Agregación Patológica de Proteínas/genética; Agregación Patológica de Proteínas/metabolismo; Agregación Patológica de Proteínas/patología; Deficiencias en la Proteostasis/genética; Deficiencias en la Proteostasis/patología

Palabras clave

Heat-shock; Neurodegenerative disease; Protein aggregation; Proteomics; Proteostasis; Ubiquitin

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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Biosíntesis de Proteínas / Caenorhabditis elegans / Mutación Missense / Proteínas de Caenorhabditis elegans / Deficiencias en la Proteostasis / Proteína Huntingtina Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: J Cell Sci Año: 2016 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido

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