Dual Role of Ribosome-Binding Domain of NAC as a Potent Suppressor of Protein Aggregation and Aging-Related Proteinopathies

The nascent polypeptide-associated complex (NAC) is a conserved ribosome-associated protein biogenesis factor. Whether NAC exerts chaperone activity and whether this function is restricted to de novo protein synthesis is unknown. Here, we demonstrate that NAC directly exerts chaperone activity toward structurally diverse model substrates including polyglutamine (PolyQ) proteins, firefly luciferase, and Aβ40. Strikingly, we identified the positively charged ribosome-binding domain in the N terminus of the βNAC subunit (N-βNAC) as a major chaperone entity of NAC. N-βNAC by itself suppressed aggregation of PolyQ-expanded proteins in vitro, and the positive charge of this domain was critical for this activity. Moreover, we found that NAC also exerts a ribosome-independent chaperone function in vivo. Consistently, we found that a substantial fraction of NAC is non-ribosomal bound in higher eukaryotes. In sum, NAC is a potent suppressor of aggregation and proteotoxicity of mutant PolyQ-expanded proteins associated with human diseases like Huntington’s disease and spinocerebellar ataxias. [Display omitted] •The protein biogenesis factor NAC exhibits broad-spectrum chaperone activity•NAC exerts a ribosome-independent chaperone function•The positively charged N terminus of βNAC is a central chaperone entity of NAC•NAC suppresses aggregation and toxicity of disease-related polyglutamine proteins NAC is a conserved protein biogenesis factor. Shen et al. demonstrate that NAC acts as a chaperone suppressing aggregation and toxicity of human disease-related polyglutamine-expanded proteins. They identify the positively charged domain of βNAC as the critical chaperone domain and show that NAC also acts independent of its ribosome association.