Distinct chaperone mechanisms can delay the formation of aggresomes by the myopathy-causing R120G αB-crystallin mutant

• Published in: Human molecular genetics 2003-07, Vol.12 (13), p.1609-1620
• Main Authors: Chávez Zobel, Aura T., Loranger, Anne, Marceau, Normand, Thériault, Jimmy R., Lambert, Herman, Landry, Jacques
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Fundamental and applied biological sciences. Psychology; Molecular and cellular biology
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/ddg173

A familial form of desmin-related myopathy (DRM) is associated with a missense mutation (R120G) in αB-crystallin (αB) and is characterized by intracellular desmin aggregation. Because αB is a molecular chaperone that participates in the assembly of desmin filaments, it has been suggested that the desmin aggregation might be due to the loss of αB function. We report here that αBR120G has indeed impaired in vivo function and structure as reflected by a highly reduced capacity to protect cells against heat shock and by an abnormal supramolecular organization even in cells not expressing desmin. In many cells, αBR120G accumulated in inclusion bodies that had characteristics of aggresomes concentrating around the centrosome following a microtubule-facilitated process. Three distinct chaperone mechanisms could reduce or even prevent the formation of the αBR120G aggresomes. Wild-type αB and Hsp27 prevented aggresome formation by co-oligomerizing with αBR120G. Hsp70 with its co-chaperone Hdj-1 or Chip-1 but not a mutant of Chip-1 lacking ubiquitin ligase activity, reduced the frequency of aggresome formation likely by targeting αBR120G for degradation. Finally, HspB8 interacted only transiently with αB but nonetheless rescued the αBR120G oligomeric organization, suggesting that it acted as a true chaperone assisting in the folding of the mutant protein. Hence, the formation of inclusion bodies in αBR120G-mediated DRM is probably due to the misfolding of αBR120G per se and can be delayed or prevented by expression of the wild type αB allele or other molecular chaperones, thereby explaining the adult onset of the disease.