Article

The impact of the unfolded protein response on human disease

Degenerative Disease Research Program, Neuroscience, Aging, and Stem Cell Research Center, Sanford Burnham Medical Research Institute, La Jolla, CA 92037, USA.
The Journal of Cell Biology (Impact Factor: 9.69). 06/2012; 197(7):857-67. DOI: 10.1083/jcb.201110131
Source: PubMed

ABSTRACT A central function of the endoplasmic reticulum (ER) is to coordinate protein biosynthetic and secretory activities in the cell. Alterations in ER homeostasis cause accumulation of misfolded/unfolded proteins in the ER. To maintain ER homeostasis, eukaryotic cells have evolved the unfolded protein response (UPR), an essential adaptive intracellular signaling pathway that responds to metabolic, oxidative stress, and inflammatory response pathways. The UPR has been implicated in a variety of diseases including metabolic disease, neurodegenerative disease, inflammatory disease, and cancer. Signaling components of the UPR are emerging as potential targets for intervention and treatment of human disease.

Download full-text

Full-text

Available from: Randal J Kaufman, Jun 19, 2015
0 Followers
 · 
351 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The unfolded protein response (UPR) - the endoplasmic reticulum stress response - is found in various pathologies including ischemia-reperfusion injury (IRI). However, its role during IRI is still unclear. Here, by combining two different bioinformatical methods - a method based on ordinary differential equations (Time Series Network Inference) and an algebraic method (probabilistic polynomial dynamical systems) - we identified the IRE1α-XBP1 and the ATF6 pathways as the main UPR effectors involved in cell's adaptation to IRI. We validated these findings experimentally by assessing the impact of their knock-out and knock-down on cell survival during IRI.
    FEBS Letters 06/2014; 588(17). DOI:10.1016/j.febslet.2014.05.065 · 3.34 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Developmental pluripotency-associated 5 (Dppa5) is an RNA binding protein highly expressed in undifferentiated pluripotent stem cells. Here, we demonstrate that Dppa5 is a regulator of hematopoietic stem cells (HSCs) that critically governs reconstitution capacity after bone marrow transplantation. Ectopic expression of Dppa5 followed by in vitro culture robustly increased HSC reconstitution levels through suppression of endoplasmic reticulum (ER) stress and apoptosis. Remarkably, a chemical chaperone that decreases ER stress in HSCs also increases HSC engraftment. Conversely, knockdown of Dppa5 impaired the long-term reconstitution ability of HSCs due to elevated ER stress levels, suggesting that ER stress regulation is physiologically important for proper HSC function in vivo. Thus, Dppa5 represents a pivotal connection between ER stress regulation and stem cell properties in HSCs. The findings also demonstrate that protein quality control is critical for the maintenance, survival, and function of HSCs in vivo and ex vivo.
    Cell Reports 05/2014; 7(5). DOI:10.1016/j.celrep.2014.04.056 · 7.21 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Hepatitis C virus (HCV) is a single-stranded, positive-sense RNA virus of clinical importance. The virus establishes a chronic infection and can progress from chronic hepatitis, steatosis to fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). The mechanisms of viral persistence and pathogenesis are poorly understood. Recently the unfolded protein response (UPR), a cellular homeostatic response to endoplasmic reticulum (ER) stress, has emerged to be a major contributing factor in many human diseases. It is also evident that viruses interact with the host UPR in many different ways and the outcome could be pro-viral, anti-viral or pathogenic, depending on the particular type of infection. Here we present evidence for the elicitation of chronic ER stress in HCV infection. We analyze the UPR signaling pathways involved in HCV infection, the various levels of UPR regulation by different viral proteins and finally, we propose several mechanisms by which the virus provokes the UPR.
    Frontiers in Microbiology 05/2014; 5:233. DOI:10.3389/fmicb.2014.00233 · 3.94 Impact Factor