Friday, November 22, 2024
11/22/2024
PROJECT SUMMARY Autophagy is a cellular, homeostatic process with important roles in aging and age-related diseases. During autophagy, cytosolic material or cargo is sequestered into autophagic vesicles called autophagosomes for subsequent lysosomal degradation; however, the underlying mechanisms for how the turover of specific types of cargo, e.g., protein aggregates or mitochondria, collectively referred to as selective autophagy, contributes to cellular proteostasis and organismal health remain elusive. We and others recently showed a conserved role for the first identified autophagy cargo receptor in metazoans, p62/SQSTM1 in mediating proteostasis and organismal benefits in an autophagy-dependent manner. In particular, we showed that p62 overexpression in the short-lived nematode C. elegans is sufficient to induce autophagy and extend life- and healthspan, and protect against protein aggregation predominantly in neurons. Moreover, p62 is selectively required for the beneficial effects of a hormetic heat shock, a conserved longevity regimen that we previously showed to induce autophagy. Collectively, these studies suggest the hypothesis that p62 plays an instructive role in inducing tissue-specific, selective autophagy to facilitate organismal benefits. This is a novel concept because autophagy receptors are traditionally viewed as factors facilitating cargo sequestration, rather than being active inducers of this complex, multi-step turnover process. We propose to address this hypothesis by using C. elegans to investigate the molecular mechanisms by which a hormetic heat shock via p62 or direct p62 overexpression regulate autophagy cell autonomously and improve organismal health via cell non-autonomous effects. Specifically, in Aim 1, we will use genetic approaches to test how a hormetic heat shock engages p62 to regulate autophagy especially in neurons. In Aim 2, we will investigate the cell-autonomous and cell non-autonomous mechanisms by which p62 induce autophagy and improve fitness. Finally, in Aim 3, we will use genetic and biochemical approaches to identify new p62-relevant cargo and p62-like receptors engaged by hormetic heat shock. These studies are significant because they will advance our knowledge of how selective autophagy contributes to organismal healthspan. These studies are innovative because they use a powerful combination of techniques and models to investigate the novel regulatory concept in the autophagy field that an autophagy receptor is sufficient to induce beneficial autophagy, potentially via cell non-autonomous mechanisms. Since autophagy plays critical roles in many human age-related disorders, understanding the regulation of autophagy and the conserved mechanisms by which autophagy affect aging in multicellular organisms like C. elegans are likely to provide new important insights relevant to aging, which also may help develop treatments for age-related diseases.
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