ER-associated degradation in health and disease - from substrate to organism.
Journal of cell science
2019; 132 (23)
Hepatic Sel1L-Hrd1 ER-associated degradation (ERAD) manages FGF21 levels and systemic metabolism via CREBH.
The EMBO journal
2018; 37 (22)
The recent literature has revolutionized our view on the vital importance of endoplasmic reticulum (ER)-associated degradation (ERAD) in health and disease. Suppressor/enhancer of Lin-12-like (Sel1L)-HMG-coA reductase degradation protein 1 (Hrd1)-mediated ERAD has emerged as a crucial determinant of normal physiology and as a sentinel against disease pathogenesis in the body, in a largely substrate- and cell type-specific manner. In this Review, we highlight three features of ERAD, constitutive versus inducible ERAD, quality versus quantity control of ERAD and ERAD-mediated regulation of nuclear gene transcription, through which ERAD exerts a profound impact on a number of physiological processes.
View details for DOI 10.1242/jcs.232850
View details for PubMedID 31792042
View details for PubMedCentralID PMC6918741
Feeding Angptl4-/- mice trans fat promotes foam cell formation in mesenteric lymph nodes without leading to ascites.
Journal of lipid research
2017; 58 (6): 1100?1113
Fibroblast growth factor 21 (Fgf21) is a liver-derived, fasting-induced hormone with broad effects on growth, nutrient metabolism, and insulin sensitivity. Here, we report the discovery of a novel mechanism regulating Fgf21 expression under growth and fasting-feeding. The Sel1L-Hrd1 complex is the most conserved branch of mammalian endoplasmic reticulum (ER)-associated degradation (ERAD) machinery. Mice with liver-specific deletion of Sel1L exhibit growth retardation with markedly elevated circulating Fgf21, reaching levels close to those in Fgf21 transgenic mice or pharmacological models. Mechanistically, we show that the Sel1L-Hrd1 ERAD complex controls Fgf21 transcription by regulating the ubiquitination and turnover (and thus nuclear abundance) of ER-resident transcription factor Crebh, while having no effect on the other well-known Fgf21 transcription factor Ppar?. Our data reveal a physiologically regulated, inverse correlation between Sel1L-Hrd1 ERAD and Crebh-Fgf21 levels under fasting-feeding and growth. This study not only establishes the importance of Sel1L-Hrd1 ERAD in the liver in the regulation of systemic energy metabolism, but also reveals a novel hepatic "ERAD-Crebh-Fgf21" axis directly linking ER protein turnover to gene transcription and systemic metabolic regulation.
View details for DOI 10.15252/embj.201899277
View details for PubMedID 30389665
View details for PubMedCentralID PMC6236331
A recellularized human colon model identifies cancer driver genes.
2016; 34 (8): 845?51
Angiopoietin-like 4 (ANGPTL4) regulates plasma triglyceride levels by inhibiting LPL. Inactivation of ANGPTL4 decreases plasma triglycerides and reduces the risk of coronary artery disease. Unfortunately, targeting ANGPTL4 for the therapeutic management of dyslipidemia and atherosclerosis is hampered by the observation that mice and monkeys in which ANGPTL4 is inactivated exhibit lipid accumulation in the mesenteric lymph nodes (MLNs). In mice these pathological events exclusively unfold upon feeding a high saturated FA diet and are followed by an ultimately lethal pro-inflammatory response and chylous ascites. Here, we show that Angptl4-/- mice fed a diet rich in trans FAs develop numerous lipid-filled giant cells in their MLNs, yet do not have elevated serum amyloid and haptoglobin, do not exhibit ascites, and survive, unlike Angptl4-/- mice fed a saturated FA-rich diet. In RAW264.7 macrophages, the saturated FA, palmitate, markedly increased markers of inflammation and the unfolded protein response, whereas the trans-unsaturated elaidate and the cis-unsaturated oleate had the opposite effect. In conclusion, trans and saturated FAs have very distinct biological effects in macrophages. Furthermore, lipid accumulation in MLNs is uncoupled from activation of an acute-phase response and chylous ascites, suggesting that ANGPTL4 should not be fully dismissed as target for dyslipidemia.
View details for DOI 10.1194/jlr.M074278
View details for PubMedID 28412693
View details for PubMedCentralID PMC5454507
A phase IIa randomized, double-blind trial of erlotinib in inhibiting epidermal growth factor receptor signaling in aberrant crypt foci of the colorectum.
Cancer prevention research (Philadelphia, Pa.)
2015; 8 (3): 222?30
Refined cancer models are needed to bridge the gaps between cell line, animal and clinical research. Here we describe the engineering of an organotypic colon cancer model by recellularization of a native human matrix that contains cell-populated mucosa and an intact muscularis mucosa layer. This ex vivo system recapitulates the pathophysiological progression from APC-mutant neoplasia to submucosal invasive tumor. We used it to perform a Sleeping Beauty transposon mutagenesis screen to identify genes that cooperate with mutant APC in driving invasive neoplasia. We identified 38 candidate invasion-driver genes, 17 of which, including TCF7L2, TWIST2, MSH2, DCC, EPHB1 and EPHB2 have been previously implicated in colorectal cancer progression. Six invasion-driver genes that have not, to our knowledge, been previously described were validated in vitro using cell proliferation, migration and invasion assays and ex vivo using recellularized human colon. These results demonstrate the utility of our organoid model for studying cancer biology.
View details for DOI 10.1038/nbt.3586
View details for PubMedID 27398792
View details for PubMedCentralID PMC4980997
Endoplasmic reticulum quality control in cancer: Friend or foe.
Seminars in cancer biology
2015; 33: 25?33
Colorectal cancer progresses through multiple distinct stages that are potentially amenable to chemopreventative intervention. Epidermal growth factor receptor (EGFR) inhibitors are efficacious in advanced tumors including colorectal cancer. There is significant evidence that EGFR also plays important roles in colorectal cancer initiation, and that EGFR inhibitors block tumorigenesis. We performed a double-blind randomized clinical trial to test whether the EGFR inhibitor erlotinib given for up to 30 days had an acceptable safety and efficacy profile to reduce EGFR signaling biomarkers in colorectal aberrant crypt foci (ACF), a subset of which progress to colorectal cancer, and normal rectal tissue. A total of 45 patients were randomized to one of three erlotinib doses (25, 50, and 100 mg) with randomization stratified by nonsteroidal anti-inflammatory drug (NSAID) use. There were no unanticipated adverse events with erlotinib therapy. Erlotinib was detected in both normal rectal mucosa and ACFs. Colorectal ACF phosphorylated ERK (pERK), phosphorylated EGFR (pEGFR), and total EGFR signaling changes from baseline were modest and there was no dose response. Overall, this trial did not meet is primary efficacy endpoint. Colorectal EGFR signaling inhibition by erlotinib is therefore likely insufficient to merit further studies without additional prescreening stratification or potentially longer duration of use.
View details for DOI 10.1158/1940-6207.CAPR-14-0148
View details for PubMedID 25604134
View details for PubMedCentralID PMC4355051
Quality control systems in the endoplasmic reticulum (ER) mediated by unfolded protein response (UPR) and endoplasmic reticulum associated degradation (ERAD) ensure cellular function and organismal survival. Recent studies have suggested that ER quality-control systems in cancer cells may serve as a double-edged sword that aids progression as well as prevention of tumor growth in a context-dependent manner. Here we review recent advances in our understanding of the complex relationship between ER proteostasis and cancer pathology, with a focus on the two most conserved ER quality-control mechanisms--the IRE1?-XBP1 pathway of the UPR and SEL1L-HRD1 complex of the ERAD.
View details for DOI 10.1016/j.semcancer.2015.02.003
View details for PubMedID 25794824
View details for PubMedCentralID PMC4523434