HSPB7 is the most potent polyQ aggregation suppressor within the HSPB family of molecular chaperones

Abstract

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.

Specific protein homeostatic functions of small heat‐shock proteins increase lifespan

“…Several protein folding diseases are characterized by the formation of toxic aggregates such as Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis. Some small HSPs have been reported to suppress the aggregation of such disease‐related proteins (Wilhelmus et al ., 2006; Carra et al ., 2008), and we have found that this is not always related to their capacity to refold heat‐denatured luciferase (Vos et al ., 2010). Therefore, we tested which of the Drosophila small HSPs could suppress aggregation of an EGFP‐tagged huntingtin exon‐1 containing 119 glutamines (EGFP‐HDQ119) in S2 cells.…”

“…Inversely, the best protector against polyQ aggregation, HSP67BC, acted independent of the HSP70 machine and was ineffective in the luciferase refolding assay. We found a similar pattern for members of the human family of small HSP proteins as well, where the efficacy to assist in HSP70‐dependent refolding was almost inversely related to the ability to prevent polyQ aggregation (Vos et al ., 2010). One can envision that transfer of nonfoldable substrates to HSP70 would result in a fatuous ATP‐driven substrate binding and release, which may slightly delay aggregation but not prevent it.…”

Proteostasis in cardiac health and disease

“…HSPB7, also referred to as cardio vascular HSP, is particularly expressed at high levels in cardiac and skeletal muscle 82 . Little is still known about its function, but HSPB7 is highly protective in cell and D. melano gaster models of polyglutamine (polyQ) dis eases in an autophagy dependent manner 87 , and protects against tachypacing induced cardiac remodelling 88 . Findings indicate that the loss of chaperone function by the HSPB5 and HSPB7 mutants causes impairment of sarcomere proteostasis and subsequent dilated cardio myopathy (DCM).…”

Small heat-shock proteins: important players in regulating cellular proteostasis

“…We have previously demonstrated that Bc prevents the aggregation of -syn, the principal protein in Lewy body deposits, and that Bc also binds to intact -syn fibrils 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 to prevent their further growth [106,107,167]. Furthermore, several sHsps (Hsp20, Hsp22, HspB7 and HspB9) inhibit the aggregation of the polyQ huntingtin protein responsible for Huntington disease and also protect against cell death triggered by the deposition of the aberrant protein [173,196]. Our subsequent studies have shown, however, that polyQ aggregation occurs in stages, and while Bc potently inhibits the first stage of fibril formation by the polyQ protein, ataxin (responsible for spinocerebellar ataxia), through interaction with its Josephin domain, the second stage of polyQ aggregation can still proceed [197].…”