Proteotoxicity

About: Proteotoxicity is a research topic. Over the lifetime, 549 publications have been published within this topic receiving 23151 citations.

Amyloid proteotoxicity initiates an inflammatory response blocked by cannabinoids.

Abstract: The beta amyloid (Aβ) and other aggregating proteins in the brain increase with age and are frequently found within neurons. The mechanistic relationship between intracellular amyloid, aging and neurodegeneration is not, however, well understood. We use a proteotoxicity model based upon the inducible expression of Aβ in a human central nervous system nerve cell line to characterize a distinct form of nerve cell death caused by intracellular Aβ. It is shown that intracellular Aβ initiates a toxic inflammatory response leading to the cell's demise. Aβ induces the expression of multiple proinflammatory genes and an increase in both arachidonic acid and eicosanoids, including prostaglandins that are neuroprotective and leukotrienes that potentiate death. Cannabinoids such as tetrahydrocannabinol stimulate the removal of intraneuronal Aβ, block the inflammatory response, and are protective. Altogether these data show that there is a complex and likely autocatalytic inflammatory response within nerve cells caused by the accumulation of intracellular Aβ, and that this early form of proteotoxicity can be blocked by the activation of cannabinoid receptors.

Temporal requirements of heat shock factor-1 for longevity assurance

Abstract: Reducing the activity of the Insulin/IGF-1 Signaling pathway (IIS) modifies development, elevates stress resistance, protects from toxic protein aggregation (proteotoxicity) and extends lifespan of worms, flies and mice. In the nematode Caenorhabditis elegans (C. elegans), lifespan extension by IIS reduction is entirely dependent upon the activity of the transcription factors DAF-16 and the Heat Shock Factor-1 (HSF-1). While DAF-16 determines lifespan exclusively during early adulthood it is required for proteotoxicity protection also during late adulthood. In contrast, HSF-1 protects from proteotoxicity during larval development. Despite the critical requirement for HSF-1 for lifespan extension the temporal requirements for this transcription factor as a lifespan determinant are unknown. To establish the temporal requirements of HSF-1 for longevity assurance we conditionally knocked down hsf-1 during larval development and adulthood of C. elegans and found that unlike daf-16, hsf-1 is foremost required for lifespan determination during early larval development, required for a lesser extent during early adulthood and has small effect on longevity also during late adulthood. Our findings indicate that early developmental events affect lifespan and suggest that HSF-1 sets during development the conditions that enable DAF-16 to promote longevity during reproductive adulthood. This study proposes a novel link between HSF-1 and the longevity functions of the IIS.

C. elegans SIRT6/7 homolog SIR-2.4 promotes DAF-16 relocalization and function during stress.

Abstract: FoxO transcription factors and sirtuin family deacetylases regulate diverse biological processes, including stress responses and longevity. Here we show that the Caenorhabditis elegans sirtuin SIR-2.4—homolog of mammalian SIRT6 and SIRT7 proteins—promotes DAF-16–dependent transcription and stress-induced DAF-16 nuclear localization. SIR-2.4 is required for resistance to multiple stressors: heat shock, oxidative insult, and proteotoxicity. By contrast, SIR-2.4 is largely dispensable for DAF-16 nuclear localization and function in response to reduced insulin/IGF-1-like signaling. Although acetylation is known to regulate localization and activity of mammalian FoxO proteins, this modification has not been previously described on DAF-16. We find that DAF-16 is hyperacetylated in sir-2.4 mutants. Conversely, DAF-16 is acetylated by the acetyltransferase CBP-1, and DAF-16 is hypoacetylated and constitutively nuclear in response to cbp-1 inhibition. Surprisingly, a SIR-2.4 catalytic mutant efficiently rescues the DAF-16 localization defect in sir-2.4 null animals. Acetylation of DAF-16 by CBP-1 in vitro is inhibited by either wild-type or mutant SIR-2.4, suggesting that SIR-2.4 regulates DAF-16 acetylation indirectly, by preventing CBP-1-mediated acetylation under stress conditions. Taken together, our results identify SIR-2.4 as a critical regulator of DAF-16 specifically in the context of stress responses. Furthermore, they reveal a novel role for acetylation, modulated by the antagonistic activities of CBP-1 and SIR-2.4, in modulating DAF-16 localization and function.

A protein quality control pathway regulated by linear ubiquitination.

Abstract: Neurodegenerative diseases are characterized by the accumulation of misfolded proteins in the brain. Insights into protein quality control mechanisms to prevent neuronal dysfunction and cell death are crucial in developing causal therapies. Here, we report that various disease-associated protein aggregates are modified by the linear ubiquitin chain assembly complex (LUBAC). HOIP, the catalytic component of LUBAC, is recruited to misfolded Huntingtin in a p97/VCP-dependent manner, resulting in the assembly of linear polyubiquitin. As a consequence, the interactive surface of misfolded Huntingtin species is shielded from unwanted interactions, for example with the low complexity sequence domain-containing transcription factor Sp1, and proteasomal degradation of misfolded Huntingtin is facilitated. Notably, all three core LUBAC components are transcriptionally regulated by Sp1, linking defective LUBAC expression to Huntington's disease. In support of a protective activity of linear ubiquitination, silencing of OTULIN, a deubiquitinase with unique specificity for linear polyubiquitin, decreases proteotoxicity, whereas silencing of HOIP has the opposite effect. These findings identify linear ubiquitination as a protein quality control mechanism and hence a novel target for disease-modifying strategies in proteinopathies.