HSF-1: Guardian of the Proteome Through Integration of Longevity Signals to the Proteostatic Network

Abstract

Discoveries made in the nematode Caenorhabditis elegans revealed that aging is under genetic control. Since these transformative initial studies, C. elegans has become a premier model system for aging research. Critically, the genes, pathways, and processes that have fundamental roles in organismal aging are deeply conserved throughout evolution. This conservation has led to a wealth of knowledge regarding both the processes that influence aging and the identification of molecular and cellular hallmarks that play a causative role in the physiological decline of organisms. One key feature of age-associated decline is the failure of mechanisms that maintain proper function of the proteome (proteostasis). Here we highlight components of the proteostatic network that act to maintain the proteome and how this network integrates into major longevity signaling pathways. We focus in depth on the heat shock transcription factor 1 (HSF1), the central regulator of gene expression for proteins that maintain the cytosolic and nuclear proteomes, and a key effector of longevity signals.

Keywords: Caenorhabditis elegans (C. elegans); HSF-1 = heat-shock factor-1; aging; cell stress and aging; genetics; longevity; proteostasis.

FIGURE 1

Proteostasis is maintain by a proteostasis network. Proteostasis has multiple levels of regulation. A great number of molecular chaperones are present in the cytosol, assisting on the appropriate folding and quality of the proteome. The proteosome and autophagy protein degradation pathways are essential for the clearance of unneeded proteins. Two distinct, but analogous, unfolded protein responses in the mitochondria and endoplasmic reticulum (mitoUPR and ER-UPR, respectively) are necessary to activate the expression of chaperones and to protect the function of these organelles from unfolding stress. Ultimately, the PN network is equipped with the adaptive activation of different transcriptional programs that get induced by different types of stress.

FIGURE 2

HSF1 post-translational modifications. Schematic of mammalian HSF1 secondary structure with post-translational modifications with known regulators and overall effect on activity. Additional modifications without known regulators are listed in Table 1. Additional regulators where a specific post-translational modification has not been identified have been omitted. “DBD” indicates the helix-turn-helix loop DNA-binding domain. “HR-A/B” and “HR-C″ identify two regions of leucine zippers. “RD” indicates the regulatory domain. “TAD” indicates the transcriptional transactivation domain. Modifications in response to heat (red arrows) or metabolic/mitogenic signals (green) are shown. Amino acid numbers are indicated. “P” indicates phosphorylation. “S” indicates sumoylation. “A” indicates acetylation.