Discovery of a ZIP7 inhibitor from a Notch pathway screen

Nolin, Erin; Gans, Sara; Llamas, Luis; Bandyopadhyay, Somnath; Brittain, Scott M.; Bernasconi-Elias, Paula; Carter, Kyle P.; Loureiro, Joseph; Thomas, Jason R.; Schirle, Markus; Yang, Yi; Guo, Ning; Roma, Guglielmo; Schuierer, Sven; Beibel, Martin; Lindeman, Alicia; Sigoillot, Frederic; Chen, Amy; Xie, Kevin; Ho, Samuel B.; Reece‐Hoyes, John S.; Weihofen, W.A.; Tyskiewicz, Kayla; Hoepfner, Dominic; McDonald, Richard I.; Guthrie, Nicolette; Dogra, Abhishek; Guo, Haibing; Shao, Jian; Ding, Jian; Canham, Stephen M.; Boynton, Geoffrey M.; George, Elizabeth; Zhao, Kang; Antczak, Christophe; Porter, Jeffery A.; Wallace, Owen B.; Tallarico, John A.; Palmer, Amy E.; Jenkins, Jeremy L.; Jain, Rishi K.; Bushell, Simon M.; Fryer, Christy J.

doi:10.1038/s41589-018-0200-7

Cited by 47 publications

(46 citation statements)

References 61 publications

(79 reference statements)

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“…SGN-LIV1A is currently in a Phase 1 trial and may be a new therapy for patients with metastatic breast cancer and cancers with LIV-1-positive indications. In addition, NVS-ZP7-4 is also recently identified as a ZIP7 inhibitor 123 . This chemical may be a potential treatment of cancer patients with high ZIP7 expression.…”

Section: Clinical Applications Of Zinc and Zinc Transportersmentioning

confidence: 99%

Zinc dysregulation in cancers and its potential as a therapeutic target

Wang

Zhao

et al. 2020

Cancer Biol. Med.

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Section: Clinical Applications Of Zinc and Zinc Transportersmentioning

confidence: 99%

Zinc dysregulation in cancers and its potential as a therapeutic target

Wang

Zhao

et al. 2020

Cancer Biol. Med.

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“…SLC39A7, the only known SLC39A family member localized on the ER membrane [ 10 ], is essential for regulation of cytosolic zinc level [ 11 ]. Previous studies have examined the role of SLC39A7 on Notch [ 21 ] and insulin signaling [ 22 – 24 ]. However, the role of SLC39A7 in phagocytosis has not been previously examined.…”

Section: Discussionmentioning

confidence: 99%

Zinc transporter SLC39A7 relieves zinc deficiency to suppress alternative macrophage activation and impairment of phagocytosis

et al. 2020

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Macrophages are key phagocytic cells and play an important role in eliminating external microorganisms and endogenous danger signals. Dysregulation in macrophage functions have been reported in patients with asthma. Zinc homeostasis is critical in maintaining macrophage functions. The solute carrier (SLC) protein SLC39A7, a Zn2+ importer, has recently been linked to asthma. However, the roles of SLC39A7 in macrophage phagocytosis are not well understood. Here we found that phagocytosis efficiency was significantly decreased in SLC39A7-knockdown THP-1 cells, however the phagocytosis capability could be reversed with zinc supplementation. SLC39A7 deficiency skewed macrophages towards alternative activation, as indicated by increased expression of M2 activation marker CD206 and decreased expression of M1 activation marker NOS2. Consistent to this result, SLC39A7knockdown cells produced reduced amounts of proinflammatory cytokines TNF-and IL-6. Furthermore, the mRNA level of receptor Clec4e previously known to be involved in phagocytosis of BCG was significantly reduced in SLC39A7 knockdown cells. Importantly, all these defects due to SLC39A7 deficiency could be reversed by zinc supplementation. Thus, zinc transporter SLC39A7 provide support for phagocytosis and classical macrophage activation.

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“…In addition, ER stress has been linked to production of CXCL1/CXCL2 and IL-1β production through interaction with RIPK1 and GSK-3β, respectively [13, 14]. Recently also Notch has been described to be involved in ER stress [31], indicating that ER stress activates multiple pathways to enhance PRR activation. In addition to directly amplifying PRR-induced responses, we here identified the suppression of the inhibitory pathways of the immune system as a new mechanism by which ER stress promotes inflammation.…”

Section: Discussionmentioning

confidence: 99%

ER stress abrogates the immunosuppressive effect of IL-10 on human macrophages through inhibition of STAT3 activation

et al. 2019

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Objective and design To determine whether ER stress affects the inhibitory pathways of the human immune system, particularly the immunosuppressive effect of IL-10 on macrophages. Material or subjects In vitro stimulation of human monocyte-derived macrophages. Treatment Cells were stimulated with TLR ligands and IL-10, while ER stress was induced using thapsigargin or tunicamycin. Methods mRNA expression was determined using qPCR, while cytokine protein production was measured using ELISA. Protein expression of receptors and transcription factors was determined using flow cytometry. Student’s t test was used for statistics. Results While under normal conditions IL-10 potently suppresses pro-inflammatory cytokine production by LPS-stimulated macrophages, we demonstrate that ER stress counteracts the immunosuppressive effects of IL-10, leading to increased pro-inflammatory cytokine production. We identified that ER stress directly interferes with IL-10R signaling by reducing STAT3 phosphorylation on Tyr705, which thereby inhibits the expression of SOCS3. Moreover, we show that ER stress also inhibits STAT3 activation induced by other receptors such as IL-6R. Conclusions Combined, these data uncover a new general mechanism by which ER stress promotes inflammation. Considering its potential involvement in the pathogenesis of diseases such as Crohn’s disease and spondyloarthritis, targeting of this mechanism may provide new opportunities to counteract inflammation.

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Discovery of a ZIP7 inhibitor from a Notch pathway screen

Abstract: The identification of activating mutations in NOTCH1 in 50% of T cell acute lymphoblastic leukemia has generated interest in elucidating how these mutations contribute to oncogenic Reprints and permissions information is available at www.nature.com/reprints.

Cited by 47 publications

References 61 publications

Zinc dysregulation in cancers and its potential as a therapeutic target

Zinc dysregulation in cancers and its potential as a therapeutic target

Zinc transporter SLC39A7 relieves zinc deficiency to suppress alternative macrophage activation and impairment of phagocytosis

ER stress abrogates the immunosuppressive effect of IL-10 on human macrophages through inhibition of STAT3 activation

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