Chemical genetic screening identifies sulfonamides that raise organellar pH and interfere with membrane traffic

Thomas J F Nieland, Yan Feng, Jing Xu Brown, Tuan Daniel Chuang, Peter D. Buckett, Jin Wang, Xiao Song Xie, Timothy E. McGraw, Tomas Kirchhausen, Marianne Wessling-Resnick

Research output: Contribution to journalArticle

26 Scopus citations

Abstract

Chemical genetics seeks to identify small molecules that afford functional dissection of cell biological pathways. Previous screens for small molecule inhibitors of exocytic membrane traffic yielded the identification and characterization of several compounds that block traffic from the Golgi to the cell surface as well as transport from the endoplasmic reticulum to the Golgi network [Feng at al. Proc Natl Acad Sci USA 2003;100:6469-6474; Yarrow et al. Comb Chem High Throughput Screen 2003;6:279-286; Feng at al. EMBO Reports 2004: in press]. Here, we screened these inhibitors for potential effects on endocytic membrane traffic. Two structurally related sulfonamides were found to be potent and reversible inhibitors of transferrin-mediated iron uptake. These inhibitors do not block endoplasmic reticulum-to-Golgi transport, but do disrupt Golgi-to-cell surface traffic. The compounds are members of a novel class of sulfonamides that elevate endosomal and lysosomal pH, down-regulate cell surface receptors, and impair recycling of internalized transferrin receptors to the plasma membrane. In vitro experiments revealed that the sulfonamides directly inhibit adenosine triphosphate (ATP) hydrolysis by the V-ATPase and that they also possess a potent proton ionophore activity. While maintenance of organellar pH is known to be a critical factor in both endocytosis and exocytosis, the precise role of acidification, beyond the uncoupling of ligands from their receptors, remains largely unknown. Identification of this novel class of sulfonamide inhibitors provides new chemical tools to better understand the function of organelle pH in membrane traffic and the activity of V-ATPases in particular.

Original languageEnglish (US)
Pages (from-to)478-492
Number of pages15
JournalTraffic
Volume5
Issue number7
DOIs
StatePublished - Jul 1 2004

Keywords

  • Chemical genetics
  • Membrane traffic
  • Organelle pH
  • Sulfonamides

ASJC Scopus subject areas

  • Structural Biology
  • Biochemistry
  • Molecular Biology
  • Genetics
  • Cell Biology

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  • Cite this

    Nieland, T. J. F., Feng, Y., Brown, J. X., Chuang, T. D., Buckett, P. D., Wang, J., Xie, X. S., McGraw, T. E., Kirchhausen, T., & Wessling-Resnick, M. (2004). Chemical genetic screening identifies sulfonamides that raise organellar pH and interfere with membrane traffic. Traffic, 5(7), 478-492. https://doi.org/10.1111/j.1398-9219.2004.00193.x