Biology subjects

Arvan, P.

Publications and source records attributed to Arvan, P..

21 records · Page 2Linked to original sources

bioRxiv2019

Requirement for TRanslocon-Associated Protein (TRAP) α in insulin biogenesis

The mechanistic basis for the biogenesis of peptide hormones and growth factors is poorly understood. Here we show that the conserved endoplasmic reticulum (ER) membrane translocon-associated protein (TRAP) , also known as signal sequence receptor 1 (SSR1)1, plays a critical role in the biosynthesis of insulin. A genetic screen in the nematode Caenorhabditis elegans revealed trap-1, which encodes the C. elegans TRAP ortholog, as a modifier of DAF-2 insulin receptor (InsR) signaling. Genetic analysis indicates that TRAP-1 acts upstream of DAF-2/InsR to control C. elegans development. Endogenous C. elegans TRAP-1 and mammalian TRAP both localized to the ER. In pancreatic beta cells, TRAP deletion impaired preproinsulin translocation but did not affect the synthesis of 1-antitrypsin, indicating that TRAP selectively influences the translocation of a subset of secreted proteins. Surprisingly, loss of TRAP function also resulted in disruption of distal steps in insulin biogenesis including proinsulin processing and secretion. These results show that TRAP assists in the ER translocation of preproinsulin and unveil unanticipated additional consequences of TRAP loss-of-function on the intracellular trafficking and maturation of proinsulin. The association of common intronic single nucleotide variants in the human TRAP gene with susceptibility to Type 2 diabetes and pancreatic beta cell dysfunction2 suggests that impairment of preproinsulin translocation and proinsulin trafficking may contribute to the pathogenesis of Type 2 diabetes.

genetics↗

bioRxiv2019

Discovery of a redox-thiol switch regulating cellular energy metabolism

Previously, we reported that increased synthesis of the gas hydrogen sulfide (H2S) during the Integrated Stress Response (ISR) induced proteome-wide cysteine-sulfhydration with the predominant modified pathway being enzymes of cellular energy metabolism (Gao, et al. 2015). Using pancreatic beta cells and quantitative proteomics in this study, we identified a Redox Thiol Switch from S-glutathionylation to S-sulfhydration and we named it, RTSGS. About half of the identified proteins are involved in energy metabolism, and one novel target was the mitochondrial phosphoenolpyruvate carboxykinase 2 (PCK2) whose catalytic Cys306was targeted by both modifications. The enzymatic activity of PCK2 was inhibited by S-glutathionylation, and this inhibition was largely reversed by S-sulfhydration. S-sulfhydration also reversed the S-glutathionylation-mediated inhibition of glucose flux, indicating a broad metabolic significance. We propose that a Redox Thiol Switch from S-glutathionylation to S-sulfhydration is a key mechanism to fine tune cellular energy metabolism in response to different levels of oxidative stress.

biochemistry↗

bioRxiv2018

Protection of circadian rhythms by the protein folding chaperone, BiP

ER stress and dysregulation of collagen synthesis are associated with progression of disease in cancer and fibrosis. Collagen synthesis is co-ordinated with the circadian clock, which curiously in cancer cells, is deregulated by ER stress. We hypothesised that interplay exists between circadian rhythm, collagen synthesis and ER stress in normal cells. Here we show that fibroblasts with ER stress do not demonstrate circadian rhythms in gene expression upon clock-synchronizing time cues. Conversely, overexpression of BiP or treatment with chemical chaperones strengthens the oscillation amplitude of circadian rhythms. The significance of these findings was explored in tendon, where we showed that BiP expression is ramped preemptively prior to a surge in collagen synthesis at night, thereby preventing protein misfolding and ER stress. In turn, we propose, this forestalls activation of the unfolded protein response in order for circadian rhythms to be maintained. Thus, targeting ER stress could be used to modulate circadian rhythm and restore collagen homeostasis in disease.

cell biology↗