Neuroendocrine control of the proteostatic network by HPK-1 delays aging

Abstract

The nervous system systemically coordinates proteostasis to maintain organismal health. In this work, we identify the transcriptional cofactor HPK-1 (homeodomain-interacting protein kinase) as a key neuronal component of the proteostatic network: its overexpression produces a paracrine signal to hyper-induce molecular chaperones and a neuroendocrine signal to induce autophagy in peripheral tissues. Neuronal HPK-1 signaling improves proteostasis in distal tissues through neurotransmitters. These pro-longevity modalities are independently regulated within serotonergic and GABAergic neurons, respectively, through distinct adaptive responses, either of which improve proteostasis in a cell non-autonomous manner. The former protects the proteome from acute stress while the latter fortifies the proteome to delay aging. Thus, HPK-1 acts as a central regulatory node upstream of the greater PN, exerting complementary roles in distinct neuronal cell-types.One-Sentence SummaryNeuronal control of proteostasis and aging