C. elegans small heat-shock protein HSP-12.6 has a highly specialized protective function towards muscle thick...

Small heat-shock proteins (sHSPs) are an ancient and diverse class of molecular chaperones, acting as a first line of defense against proteotoxic stresses. While the canonical sHSPs prevent uncontrollable aggregation of a broad range of non-native substrates, a subset of sHSPs do not exhibit this broad activity in vitro, and their functions in vivo are poorly understood. Interestingly, several such sHSPs are selectively expressed in muscle tissues, including by myogenic programs, indicating likely functional roles. We examined in vivo function of C. elegans HSP-12.6, which possesses no chaperone activity in vitro but regulates lifespan, and is developmentally induced in the muscles of long-lived dauer animals. We found that HSP-12.6 exhibits exceptional selectivity in protecting the muscle function against folding or assembly mutations in thick filament proteins, but not in thin filament or non-filament proteins. This reflected its exclusive chaperone-like binding to the healthy myosin-containing thick filaments, and to their aggregates. HSP-12.6 did not bind other muscle structures or aggregates, including those of thin filaments, and retained its selectivity to either healthy thick filaments or their aggregates when challenged with a toxic aggregation-prone polyQ protein. Our data establish HSP-12.6 as a highly-selective myoprotective chaperone, with client spectrum distinct from other sHSPs.