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PNAS 102 (34): 12141-12146

Copyright © 2005 by the National Academy of Sciences.

GENETICS

Arrestin-related proteins mediate pH signaling in fungi

Silvia Herranz *, José M. Rodríguez * {dagger}, Henk-Jan Bussink {ddagger}, Juan C. Sánchez-Ferrero *, Herbert N. Arst, Jr. {ddagger}, Miguel A. Peñalva *, and Olivier Vincent *, §

*Departamento de Microbiología Molecular, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Madrid 28040, Spain; and {ddagger}Department of Infectious Diseases, Faculty of Medicine, Imperial College London, Du Cane Road, London W12 0NN, United Kingdom

Edited by Robert J. Lefkowitz, Duke University Medical Center, Durham, NC, and approved July 10, 2005

Received for publication June 8, 2005.

Abstract: Metazoan arrestins bind to seven-transmembrane (7TM) receptors to regulate function. Aspergillus nidulans PalF, a protein involved in the fungal ambient pH signaling pathway, contains arrestin N-terminal and C-terminal domains and binds strongly to two different regions within the C-terminal cytoplasmic tail of the 7TM, putative pH sensor PalH. Upon exposure to alkaline ambient pH, PalF is phosphorylated and, like mammalian {beta}-arrestins, ubiquitinated in a signal-dependent and 7TM protein-dependent manner. Substitution in PalF of a highly conserved arrestin N-terminal domain Ser residue prevents PalF-PalH interaction and pH signaling in vivo. Thus, PalF is the first experimentally documented fungal arrestin-related protein, dispelling the notion that arrestins are restricted to animal proteomes. Epistasis analyses demonstrate that PalF posttranslational modification is partially dependent on the 4TM protein PalI but independent of the remaining pH signal transduction pathway proteins PalA, PalB, and PalC, yielding experimental evidence bearing on the order of participation of the six components of the pH signal transduction pathway. Our data strongly implicate PalH as an ambient pH sensor, possibly with the cooperation of PalI.

Key Words: seven-transmembrane receptor • signal transduction • ubiquitination • Aspergillus • endocytosis

Author contributions: O.V. designed research; S.H., J.M.R., H.-J.B., H.N.A., and O.V. performed research; J.C.S.-F. contributed new reagents/analytical tools; S.H., J.M.R., H.N.A., M.A.P., and O.V. analyzed data; and H.N.A., M.A.P., and O.V. wrote the paper.

This paper was submitted directly (Track II) to the PNAS office.

Abbreviations: PFAM, Protein Families Database of Alignments and Hidden Markov Models; HA, hemagglutinin; GAD, Gal4 activation domain; 7TM, seven-transmembrane; ESCRT, endosomal sorting complexes required for transport.

{dagger} Present address: Laboratory of Biochemical Genetics and Metabolism, The Rockefeller University, 1230 York Avenue, New York, NY 10021.

§ To whom correspondence should be addressed. E-mail: ovincent{at}cib.csic.es.

© 2005 by The National Academy of Sciences of the USA

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