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Stony Brook, NY, United States

Li F.-Q.,SUNY at Stony Brook | Mofunanya A.,Graduate Program in Genetics | Fischer V.,Graduate Program in Molecular and Cellular Pharmacology | Hall J.,SUNY at Stony Brook | Takemaru K.-I.,SUNY at Stony Brook
Molecular Biology of the Cell | Year: 2010

In the canonical Wnt pathway, β-catenin acts as a key coactivator that stimulates target gene expression through interaction with Tcf/Lef transcription factors. Its nuclear accumulation is the hallmark of active Wnt signaling and is frequently associated with cancers. Chibby (Cby) is an evolutionarily conserved molecule that represses β-catenin-dependent gene activation. Although Cby, in conjunction with 14-3-3 chaperones, controls β-catenin distribution, its molecular nature remains largely unclear. Here, we provide compelling evidence that Cby harbors bona fide nuclear localization signal (NLS) and nuclear export signal (NES) motifs, and constitutively shuttles between the nucleus and cytoplasm. Efficient nuclear export of Cby requires a cooperative action of the intrinsic NES, 14-3-3, and the CRM1 nuclear export receptor. Notably, 14-3-3 docking provokes Cby binding to CRM1 while inhibiting its interaction with the nuclear import receptor importin-α, thereby promoting cytoplasmic compartmentalization of Cby at steady state. Importantly, the NLS- and NES-dependent shuttling of Cby modulates the dynamic intracellular localization of β-catenin. In support of our model, short hairpin RNA-mediated knockdown of endogenous Cby results in nuclear accumulation of β-catenin. Taken together, these findings unravel the molecular basis through which a combinatorial action of Cby and 14-3-3 proteins controls the dynamic nuclear-cytoplasmic trafficking of β-catenin. © 2010 by The American Society for Cell Biology. Source

Sun S.,University of Texas Southwestern Medical Center | Lourie R.,Materials Medical Research Institute | Goodrich J.K.,Graduate Program in Genetics | Poole A.C.,Cornell University | And 5 more authors.
Molecular Biology of the Cell | Year: 2016

Inflammatory bowel disease (IBD) is an incurable chronic idiopathic disease that drastically decreases quality of life. Endoplasmic reticulum (ER)-associated degradation (ERAD) is responsible for the clearance of misfolded proteins; however, its role in disease pathogenesis remains largely unexplored. Here we show that the expression of SEL1L and HRD1, the most conserved branch of mammalian ERAD, is significantly reduced in ileal Crohn's disease (CD). Consistent with this observation, laboratory mice with enterocyte-specific Sel1L deficiency (Sel1LδIEC) develop spontaneous enteritis and have increased susceptibility to Toxoplasma gondii- induced ileitis. This is associated with profound defects in Paneth cells and a disproportionate increase of Ruminococcus gnavus, a mucolytic bacterium with known association with CD. Surprisingly, whereas both ER stress sensor IRE1α and effector CHOP are activated in the small intestine of Sel1LδIEC mice, they are not solely responsible for ERAD deficiency-associated lesions seen in the small intestine. Thus our study points to a constitutive role of Sel1L-Hrd1 ERAD in epithelial cell biology and the pathogenesis of intestinal inflammation in CD. © 2016 Sun et al. Source

Atamian H.S.,Graduate Program in Genetics | Chaudhary R.,Graduate Program in Genetics | Girke T.,Graduate Program in Genetics | Kaloshian I.,Graduate Program in Genetics | Kaloshian I.,University of California at Riverside
Molecular Plant-Microbe Interactions | Year: 2013

The interactions between aphids and their host plants seem to be analogous to those of plant-microbial pathogens. Unlike microbial pathogen effectors, little is known about aphid effectors and their ability to interfere with host immunity. To date, only three functional aphid effectors have been reported. To identify potato aphid (Macrosiphum euphorbiae) effectors, we developed a salivary gland transcriptome using Illumina technology. We generated 85 million Illumina reads from salivary glands and assembled them into 646 contigs. Ab initio sequence analysis predicted secretion signal peptides in 24% of these sequences, suggesting that they might be secreted into the plant during aphid feeding. Eight of these candidate effectors with secretion signal peptides were functionally characterized using Agrobacterium tumefaciens- mediated transient overexpression in Nicotiana benthamiana. Two candidate effectors, Me10 and Me23, increased aphid fecundity, suggesting their ability to suppress N. benthamiana defenses. Five of these candidate effectors, including Me10 and Me23, were also analyzed in tomato by delivering them through the Pseudomonas syringae type three secretion system. In tomato, only Me10 increased aphid fecundity. This work identified two additional aphid effectors with ability to manipulate the host for their advantage. © 2013 The American Phytopathological Society. Source

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