Heat Stress Produces Lasting Cellular Resilience via Formation of Tetraspanin Webs
Research has shown that many forms of mild, transient stress result in lasting changes to cell behavior and modestly slowed aging in short-lived animal species. This is the case whether the stress involves heat, cold, or lack of nutrients. This is hormesis, that overall benefit can result from suffering mild stress and low levels of molecular damage. While researchers have identified improved activity of the cell maintenance processes of autophagy as an important mechanism in the beneficial response to mild stressors, it remains a work in progress to understand all of the details of the lasting hormetic response to transient stress.
In today's open access paper, researchers discover a novel way in which cells maintain a memory of their exposure to heat stress. The protein TSP-1 is a tetraspanin, and this type of protein is known to form arrangements known as webs in the cell membrane. When generated in response to heat stress these tetraspanin webs can be long-lasting, and thus provide the cell with a form of memory distinct from epigenetic marks or other changes affecting gene expression in the cell nucleus. In general, one might argue that complex structures that form in the cell membrane (such as lipid rafts) are understudied and poorly understood in comparison to the biochemistry of the cell nucleus.
Early-life stress triggers long-lasting organismal resilience and longevity via tetraspanin
Epidemiological and clinical studies in humans show that life stress of various forms can exert profound lasting impacts on mental and physical health outcomes and life spans. Milder physiological stresses, such as fasting with adequate nutrition or thermal stimuli via sauna exposure, are associated with long-lasting health benefits. Transient periods of stress can induce persistent changes in the endocrine response, epigenetic regulation of gene expression, and plasticity changes in various organs. However, the underlying molecular and cellular mechanisms by which transient early-life stress can produce memory-like physiological effects remain poorly understood.
The free-living nematode Caenorhabditis elegans has emerged as a tractable model system to study how early-life stress may affect adult phenotypes. Adults that have undergone the dauer stage preserve a memory of their early-life starvation experience, resulting in alterations in gene expression, extended life span, and decreased reproductive capacity. In addition, a 1-day shift from 20° to 25°C during early adulthood in C. elegans appears to improve stress resistance and extend life span through known stress-responding transcription factors: Forkhead box transcription factor (DAF-1), heat shock transcription factor (HSF-1), and hypoxia inducible transcription factor (HIF-1). It remains unclear how specific effectors of these transcription factors, or other epigenetic mechanisms independent of these factors, may elicit long-lasting impacts on adult stress resilience and longevity.
In this study, we use a robust thermal stress paradigm in C. elegans to uncover causal mechanisms by which transient stress may exert lasting impacts on organismal resilience and longevity. We show that transient heat exposure at 28°C during late larval development activates the gene tsp-1, which encodes a C. elegans homolog of the evolutionarily conserved tetraspanin protein family. Tetraspanin 1 (TSP-1) proteins form tetraspanin web-like structures and are essential for maintaining membrane permeability, barrier functions, and heat-induced organismal resilience and longevity. Initial induction of tsp-1 by heat requires the histone acetyltransferase CBP/p300 homolog (CPB-1); however, unexpectedly, this results in sustained up-regulation of TSP-1 protein without a corresponding increase in mRNA abundance.
Our data suggest that tsp-1 expression leads to TSP-1 protein multimerization and the formation of stable tetraspanin web structures, which persist even in the absence of initial stimuli and tsp-1 transcript up-regulation. This tetraspanin web-based stable protein structure formation represents an intriguing mechanism of cellular memory, distinct from previously known modes of epigenetic regulation primarily occurring in the nucleus, such as DNA and histone modifications.