Transcriptional Regulation of the Proteostatic Network
Figure 1. HPK-1 promotes protein homeostasis. See Das et al. (2017) PLoS Genetics for additional supporting experiments.
The mechanisms that maintain proteome folding and function (proteostasis), become ineffective during normal aging, contributing to the onset and progression of neurodegenerative protein misfolding diseases- including Alzheimer’s Disease. Proteostasis is sustained through integrated processes involving coordinated regulation of protein synthesis, folding, and degradation in response to diverse signals. We have identified the homeodomain-interacting protein kinase (HPK-1) as a key regulator of aging and proteostasis (Das et al. 2017 PLoS Genetics). Constitutive expression of hpk-1, is sufficient to delay aging, preserve proteostasis, and promote stress resistance, while loss of hpk-1 impairs stress resistance, accelerating aging and the deterioration of the proteome (Figure 1). HPK-1 acts via the heat shock transcription factor (HSF-1), and the target of rapamycin complex 1 (TORC1). HPK-1 antagonizes sumoylation of HSF-1, presumably to repress gene expression. HPK-1 extends longevity by an additional independent mechanism: induction of autophagy via dietary restriction or TORC1 inactivation. HPK-1 expression is itself regulated by distinct mechanisms after nutritional or thermal stress, implying that HPK-1 may function as part of an integrated stress response to maintain proteostasis (Figure 2). Notably, a recent study found induced expression of a mammalian homolog in regions of the brain affected by neurodegeneration in Alzheimer’s Disease and Amyotrophic Lateral Sclerosis patients, suggesting an induced stress response.
Figure 2. HPK-1 delays aging and maintains proteostasis by potentiating TORC1 mediated autophagy and blocking HSF-1 inactivation through sumoylation. (from Das et al. (2017) PLoS Genetics).
A major goal of this project is to understand how HPK-1 functions as a part of an integrated system to maintain proteome function. We are utilizing genetic, genomic, and systems biology approaches to explore how dynamic regulation of the proteostatic network safeguards proper function of the proteome. In addition, we are employing tissue-specific gene manipulation to understand how this network acts across tissues. With this work we will gain understanding of the role of HPK-1 during aging in the regulation of the proteostatic network, and insight into the manifestation of neurodegenerative diseases.
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