bims-unfpre 2019-10-06 papers

Issue of 2019‒10‒06
three papers selected by
Susan Logue
University of Manitoba

Front Biosci (Landmark Ed). 2020 Jan 01. 25 536-548

Blocking PERK resuces vascular smooth muscle cells from homocysteine-induced ER stress and apoptosis.

Wei Li, Fujun Shang, Xiaoli Li, Shaoping Lu, Xiaolin Niu, Zhimin Zhang, Jing Liu, Xue Li, Lianyou Zhao.

Hyperhomocysteinemia induces stress response in endoplasmic reticulum (ERS). Here, we tested whether blockage of homocysteine (Hcy) induced ERS and subsequent apoptosis in vascular smooth muscle cells can be inhibited by blockage of PERK/eIF2α/ATF4/CHOP signaling. Short-term exposure of vascular smooth muscle cells to Hcy led to the phosphorylation of PERK (pPERK), which in turn, phosphorylated eIF2 alpha (peIF2a) and inhibited the unfolded protein response. Long-term Hcy exposure, however, increased the expression of ATF-4 and CHOP and led to apoptosis. Treatment of cells with salubrinal, a specific inhibitor for eIF2a decreased the expression of ATF-4 and CHOP, and prevented apoptosis. Together, the results show that PERK pathway is involved in Hcy-induced vascular smooth muscle cell apoptosis and that blocking the PERK pathway protects against this injury.

Nat Commun. 2019 Sep 30. 10(1): 4443

Constitutive XBP-1s-mediated activation of the endoplasmic reticulum unfolded protein response protects against pathological tau.

Sarah M Waldherr, Timothy J Strovas, Taylor A Vadset, Nicole F Liachko, Brian C Kraemer.

To endure over the organismal lifespan, neurons utilize multiple strategies to achieve protein homeostasis (proteostasis). Some homeostatic mechanisms act in a subcellular compartment-specific manner, but others exhibit trans-compartmental mechanisms of proteostasis. To identify pathways protecting neurons from pathological tau protein, we employed a transgenic Caenorhabditis elegans model of human tauopathy exhibiting proteostatic disruption. We show normal functioning of the endoplasmic reticulum unfolded protein response (UPRER) promotes clearance of pathological tau, and loss of the three UPRER branches differentially affects tauopathy phenotypes. Loss of function of xbp-1 and atf-6 genes, the two main UPRER transcription factors, exacerbates tau toxicity. Furthermore, constitutive activation of master transcription factor XBP-1 ameliorates tauopathy phenotypes. However, both ATF6 and PERK branches of the UPRER participate in amelioration of tauopathy by constitutively active XBP-1, possibly through endoplasmic reticulum-associated protein degradation (ERAD). Understanding how the UPRER modulates pathological tau accumulation will inform neurodegenerative disease mechanisms.

DOI: https://doi.org/10.1038/s41467-019-12070-3

RNA Biol. 2019 Oct 01. 1-15

Human cells adapt to translational errors by modulating protein synthesis rate and protein turnover.

Ana Sofia Varanda, Mafalda Santos, Ana R Soares, Rui Vitorino, Patrícia Oliveira, Carla Oliveira, Manuel A S Santos.

Deregulation of tRNAs, aminoacyl-tRNA synthetases (aaRS) or tRNA modifying enzymes, increase the level of protein synthesis errors (PSE) and are associated with several diseases, but the cause-effect mechanisms of these pathologies remain elusive. To clarify the role of PSE in human biology, we have engineered a HEK293 cell line to overexpress a wild type (Wt) tRNASer and two tRNASer mutants that misincorporate serine at non-cognate codon sites. Then, we followed long-term adaptation to PSE of such recombinant cells by analysing cell viability, protein synthesis rate and activation of protein quality control mechanisms (PQC). Engineered cells showed higher level of misfolded and aggregated proteins; activated the ubiquitin-proteasome system (UPS) and the unfolded protein response (UPR), indicative of proteotoxic stress. Adaptation to PSE involved increased protein turnover, UPR up-regulation and altered protein synthesis rate. Gene expression analysis showed that engineered cells presented recurrent alterations in the endoplasmic reticulum, cell adhesion and calcium homeostasis. Herein, we unveil new phenotypic consequences of protein synthesis errors in human cells and identify the protein quality control processes that are necessary for long-term adaptation to PSE and proteotoxic stress. Our data provide important insight on how chronic proteotoxic stress may cause disease and highlight potential biological pathways that support the association of PSE with disease.

Keywords: Protein synthesis errors; human cells; protein quality control; tRNAs; ubiquitin-proteasome system; unfolded protein response

DOI: https://doi.org/10.1080/15476286.2019.1670039