Rhomboid cleaves Star to regulate the levels of secreted Spitz.
Intracellular trafficking of the precursor of Spitz (Spi), the major Drosophila EGF receptor (EGFR) ligand, is facilitated by the chaperone Star, a type II transmembrane protein. This study identifies a novel mechanism for modulating the activity of Star, thereby influencing the levels of active Spi ligand produced. We demonstrate that Star can efficiently traffic Spi even when present at sub-stoichiometric levels, and that in Drosophila S(2)R(+) cells, Spi is trafficked from the endoplasmic reticulum to the late endosome compartment, also enriched for Rhomboid, an intramembrane protease. Rhomboid, which cleaves the Spi precursor, is now shown to also cleave Star within its transmembrane domain both in cell culture and in flies, expanding the repertoire of known Rhomboid substrates to include both type I and type II transmembrane proteins. Cleavage of Star restricts the amount of Spi that is trafficked, and may explain the exceptional dosage sensitivity of the Star locus in flies.
Tsruya
Rachel
R
Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
Wojtalla
Alexandra
A
Carmon
Shari
S
Yogev
Shaul
S
Reich
Aderet
A
Bibi
Eitan
E
Merdes
Gunter
G
Schejter
Eyal
E
Shilo
Ben-Zion
BZ
D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D004330:Drosophila / Q000196:embryology / Q000235:genetics / Q000378:metabolism; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004625:Embryo, Nonmammalian / Q000378:metabolism; D011992:Endosomes / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000235:genetics / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007763:Lac Operon / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D011485:Protein Binding; D021381:Protein Transport; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D014162:Transfection
D029721:Drosophila Proteins; D008565:Membrane Proteins; D011993:Recombinant Fusion Proteins; C081481:Rho protein, Drosophila; C415248:S protein, Drosophila; D049452:Green Fluorescent Proteins; C076026:spi protein, Drosophila; D004815:Epidermal Growth Factor; D066246:ErbB Receptors