HSPB7 is the most potent polyQ aggregation suppressor within the HSPB family of molecular chaperones.
A small number of heat-shock proteins have previously been shown to act protectively on aggregation of several proteins containing an extended polyglutamine (polyQ) stretch, which are linked to a variety of neurodegenerative diseases. A specific subfamily of heat-shock proteins is formed by the HSPB family of molecular chaperones, which comprises 10 members (HSPB1-10, also called small HSP). Several of them are known to act as anti-aggregation proteins in vitro. Whether they also act protectively in cells against polyQ aggregation has so far only been studied for few of them (e.g. HSPB1, HSPB5 and HSPB8). Here, we compared the 10 members of the human HSPB family for their ability to prevent aggregation of disease-associated proteins with an expanded polyQ stretch. HSPB7 was identified as the most active member within the HSPB family. It not only suppressed polyQ aggregation but also prevented polyQ-induced toxicity in cells and its expression reduces eye degeneration in a Drosophila polyQ model. Upon overexpression in cells, HSPB7 was not found in larger oligomeric species when expressed in cells and-unlike HSPB1-it did not improve the refolding of heat-denatured luciferase. The action of HSPB7 was also not dependent on the Hsp70 machine or on proteasomal activity, and HSPB7 overexpression alone did not increase autophagy. However, in ATG5-/- cells that are defective in macroautophagy, the anti-aggregation activity of HSPB7 was substantially reduced. Hence, HSPB7 prevents toxicity of polyQ proteins at an early stage of aggregate formation by a non-canonical mechanism that requires an active autophagy machinery.
Vos
Michel J
MJ
Department of Cell Biology, Section of Radiation and Stress Cell Biology, University of Groningen, Ant. Deusinglaan 1, Groningen, The Netherlands.
Zijlstra
Marianne P
MP
Kanon
Bart
B
van Waarde-Verhagen
Maria A W H
MA
Brunt
Ewout R P
ER
Oosterveld-Hut
Hendrika M J
HM
Carra
Serena
S
Sibon
Ody C M
OC
Kampinga
Harm H
HH
D000818:Animals; D001343:Autophagy; D015153:Blotting, Western; D002460:Cell Line; D004330:Drosophila; D015870:Gene Expression; D055551:HSP27 Heat-Shock Proteins / Q000235:genetics* / Q000378:metabolism*; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D050888:Heat-Shock Proteins, Small / Q000378:metabolism*; D006801:Humans; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D010455:Peptides / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding; D020539:Sequence Analysis, Protein
D055551:HSP27 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins; C550985:HSPB7 protein, human; D050888:Heat-Shock Proteins, Small; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; C097188:polyglutamine; D046988:Proteasome Endopeptidase Complex