Foamy Virus Envelope Protein Is a Substrate for Signal Peptide Peptidase-like 3 (SPPL3)*

  1. Regina Fluhrer‡§,3
  1. From the ‡Adolf Butenandt Institute for Biochemistry, Ludwig-Maximilians University Munich,
  2. the §German Center for Neurodegenerative Diseases (DZNE), and
  3. the ‖Munich Cluster for Systems Neurology (SyNergy), 80336 Munich, Germany,
  4. the Institute of Molecular Immunology, Helmholtz Zentrum München, German Research Center for Environmental Health and
  5. **Technische Universität München, 81377 Munich, Germany, and
  6. the ‡‡Biochemical Institute, Christian-Albrechts University Kiel, 24118 Kiel, Germany
  1. ↵3 To whom correspondence should be addressed: Adolf Butenandt Institute for Biochemistry, Ludwig-Maximilians University Munich and DZNE, Schillerstr. 44, D-80336 Munich, Germany. Tel.: 49-89-2180-75487; Fax: 49-89-2180-75415; E-mail: regina.fluhrer{at}dzne.lmu.de.

Background: SPPL proteases are intramembrane-cleaving aspartyl proteases of the GxGD type.

Results: Under certain circumstances, SPPL3 cleaves FVenv independent of prior shedding, generating substrates for subsequent intramembrane proteolysis.

Conclusion: Unlike other known GxGD proteases, SPPL3 can act as a sheddase and an intramembrane protease within the regulated intramembrane proteolysis cascade.

Significance: This initial biochemical characterization of SPPL3 will help to address its physiological role in later studies.

Abstract

Signal peptide peptidase (SPP), its homologs, the SPP-like proteases SPPL2a/b/c and SPPL3, as well as presenilin, the catalytic subunit of the γ-secretase complex, are intramembrane-cleaving aspartyl proteases of the GxGD type. In this study, we identified the 18-kDa leader peptide (LP18) of the foamy virus envelope protein (FVenv) as a new substrate for intramembrane proteolysis by human SPPL3 and SPPL2a/b. In contrast to SPPL2a/b and γ-secretase, which require substrates with an ectodomain shorter than 60 amino acids for efficient intramembrane proteolysis, SPPL3 cleaves mutant FVenv lacking the proprotein convertase cleavage site necessary for the prior shedding. Moreover, the cleavage product of FVenv generated by SPPL3 serves as a new substrate for consecutive intramembrane cleavage by SPPL2a/b. Thus, human SPPL3 is the first GxGD-type aspartyl protease shown to be capable of acting like a sheddase, similar to members of the rhomboid family, which belong to the class of intramembrane-cleaving serine proteases.

Footnotes

  • ↵1 Supported by a Ph.D. fellowship from the Hans und Ilse Breuer Stiftung and by the Elitenetwork of Bavaria within the Graduate Program “Protein Dynamics in Health and Disease.”

  • ↵2 Member of the Center for Integrated Protein Science Munich (CIPSM). Supported by a “Forschungsprofessur” from the Ludwig-Maximilians University.

  • ↵* This work was supported in part by Deutsche Forschungsgemeinschaft Grant HA 1737-11 (to R. F. and C. H.) and the Competence Network for Neurodegenerative Diseases (KNDD) of the Bundesministerium für Bildung und Forschung.

  • ↵Graphic This article contains supplemental Figs. S1 and S2.

  • Received April 11, 2012.
  • Revision received October 26, 2012.
View this article with LENS
Table of Contents

This Article

  1. First Published on November 6, 2012 doi: 10.1074/jbc.M112.371369 The Journal of Biological Chemistry 287, 43401-43409.
  1. » Abstract(Free)
  2. Full Text(Free)
  3. PDF(Free)
  4. PDF including Supp Data
  5. Supplemental Data
  6. All Versions of this Article:
    1. M112.371369v1
    2. 287/52/43401 (most recent)

Classifications

Article Usage Stats

  1. Article Usage Statistics

Submit your work to JBC.

You'll be in good company.