Biology subjects

Urban, N. D.

Publications and source records attributed to Urban, N. D..

3 recordsLinked to original sources

bioRxiv2025

Functionally diversified BiP orthologs control body growth, reproduction, stress resistance, aging, and ER-Phagy in Caenorhabditis elegans.

Cellular systems that govern protein folding rely on a delicate balance of functional redundancy and diversification to maintain protein homeostasis (proteostasis). Here, we use Caenorhabditis elegans to demonstrate how both overlapping and divergent activities of two homologous endoplasmic reticulum (ER)-resident HSP70 family chaperones, HSP-3 and HSP-4, orchestrate ER proteostasis and contribute to organismal physiology. We identify tissue-, age-, and stress-specific protein expression patterns and find both redundant and distinct functions for HSP-3 and HSP-4 in ER stress resistance, reproduction, and body size regulation. We show that only HSP-3 overexpression is sufficient to improve longevity and that loss of HSP-3 or HSP-4 during distinct stages of the worm cycle or specific tissues have opposing effects on worm lifespan. Furthermore, we find that loss of HSP-4, but not HSP-3, improves tolerance to protein aggregation induced-stress by activating ER-Phagy through the engagement of IRE-1 and the putative ER-Phagy receptor, C18E9.2. Mechanistically, we show that de-repression of IRE-1 via HSP-4 dissociation allows for direct inhibition of C18E9.2- mediated ER-Phagy and demonstrate that a conserved orthologous mechanism involving the respective human orthologs, BiP, Sec-62, and IRE-1, contributes to ER proteostasis regulation in human cells. Taken as a whole, our study demonstrates that functional diversification of orthologous proteins within a single organelle is an efficient mechanism to maximize stress resilience while also defining a novel link between ER- phagy and proteostasis regulation.

physiology↗

bioRxiv2024

C. elegans behavior, fitness, and lifespan, are modulated by AWB/ASH-dependent death perception.

The ability of the nervous system to initiate intricate goal-directed behaviors in response to environmental stimuli is essential for metazoan survival. In this study, we demonstrate that the nematode Caenorhabditis elegans perceives and reacts to dead conspecifics. The exposure to C. elegans corpses as well as corpse lysates activates sensory neurons AWB and ASH, triggering a glutamate-and acetylcholine-dependent signaling cascade that regulates both immediate (aversion) and long-term (survival) responses to the presence of a death signature. We identify increased adenosine monophosphate (AMP) and cysteine concentrations as chemical fingerprints for the presence of metazoan corpses and show that death cue sensing by AWB and ASH leads to physiological changes which promote reproduction at the expense of lifespan. Our findings illuminate a novel signaling paradigm that allows organisms to detect and interpret the environmental enrichment of intracellular metabolites as a death cue.

animal behavior and cognition↗

bioRxiv2024

FICD deficiency protects mice from hypertrophy-induced heart failure via BiP-mediated activation of the UPRER and ER-phagy

Cardiomyocytes require the HSP70 chaperone BiP to maintain proteostasis in the endoplasmic reticulum (ER) following cardiac stress. The adenylyl transferase (AMPylase) FICD is increasingly recognized to regulate BiP activity through the post-translational addition of an adenosine monophosphate moiety to BiP surface residues. However, the physiological impact of FICD-mediated BiP regulation in the context of cardiovascular health is unknown. Here, we find that FICD deficiency prevents pressure overload-associated heart failure, hypertrophy, and fibrosis, and that FICD knockout mice maintain normal cardiac function after cardiac pressure overload. At a cellular level, we observe that FICD-mediated BiP AMPylation blunts the induction of the unfolded protein response (UPRER) and impairs BiP interaction with FAM134B, an ER-phagy receptor, thus limiting ER-phagy induction under stress. In contrast, FICD loss significantly increases BiP-dependent UPRER induction and ER-phagy in stressed cardiomyocytes. We also uncover cell type-specific consequences of FICD activity in response to ER stress, positioning FICD as a critical proteostasis regulator in cardiac tissue. Our results highlight a novel regulatory paradigm controlling stress resilience in cardiomyocytes and offer a rationale to consider FICD as a therapeutic target to treat cardiac hypertrophy.

cell biology↗