Aging is characterized by irreversible and stochastic accumulation of damaged and aberrant proteins that impact most physiological functions. Accumulating evidence suggests that longevity is closely tied to the ability of the organism to effectively overcome stress. To deal with stress, organisms have evolved specific mechanisms, including the heat shock stress response, unfolded protein response and the ubiquitin proteasome system, all of which ensure the maintenance of protein homeostasis. In the heat shock response system, heat shock protein 90 (Hsp90) plays a key role as a chaperone in protecting the folding of newly synthesized proteins, while directing the damaged ones to degradation. Although, previous reports have outlined the molecular basis of Hsp90 regulation, its contribution to immune senescence accompanying aging remains largely unexplored. We now describe experiments supporting the hypothesis that aging affects HSP90 function by altering the landscape of co-chaperone and client protein interactome, through specific post-translational modifications. Our results demonstrate that age-associated alterations in Hsp90-client protein interactions directly contribute to the altered kinetics of ligand-induced TCR internalization, intracellular Ca2+ flux and F-actin polymerization, influencing T cell functional responses. Surprisingly, despite defects in the interaction and function of Hsp90 and non-muscle myosin IIA, increased migration towards SDF-• is observed in T cells from the elderly. We now demonstrate that increased chemotactic migratory index in T cells correlates with increased surface expression of CXCR4, attributable to altered ubiquitination dynamics.
Thus, age-associated alterations in the regulation of Hsp90 contribute to immune senescence, directly through its regulation of signaling networks within T lymphocytes and indirectly, through its impact on folding and release of client proteins. Therefore, manipulation of Hsp90 may serve as a potential target to ameliorate immune dysfunction accompanying aging.
|Commitee:||Das, Kumuda, Morrison, Richard, O'Brien, Charles, Soderberg, Lee|
|School:||University of Arkansas for Medical Sciences|
|Department:||Microbiology and Immunology|
|School Location:||United States -- Arkansas|
|Source:||DAI-B 72/12, Dissertation Abstracts International|
|Subjects:||Cellular biology, Immunology|
|Keywords:||Hsp90, Immune senescence, Migration, Proteostasis|
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