Proteomic Characterization of the Heart and Skeletal Muscle Reveals Widespread Arginine ADP-Ribosylation by the ARTC1 Ectoenzyme

Mario Leutert; Stephan Menzel; Rickmer Braren; Björn Rissiek; Ann-Katrin Hopp; Kathrin Nowak; Lavinia Bisceglie; Peter Gehrig; Hui Li; Anna Zolkiewska; Friedrich Koch-Nolte; Michael O Hottiger

doi:10.1016/j.celrep.2018.07.048

Proteomic Characterization of the Heart and Skeletal Muscle Reveals Widespread Arginine ADP-Ribosylation by the ARTC1 Ectoenzyme

Cell Rep. 2018 Aug 14;24(7):1916-1929.e5. doi: 10.1016/j.celrep.2018.07.048.

Authors

Affiliations

¹ Department of Molecular Mechanisms of Disease, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland; Molecular Life Science PhD Program of the Life Science Zurich Graduate School, Winterthurerstrasse 190, 8057 Zurich, Switzerland.
² Institute of Immunology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany.
³ Functional Genomics Center Zurich, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland.
⁴ Department of Biochemistry and Molecular Biophysics, Kansas State University, 141 Chalmers Hall, Manhattan, KS 66506, USA.
⁵ Institute of Immunology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany. Electronic address: [email protected].
⁶ Department of Molecular Mechanisms of Disease, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland. Electronic address: [email protected].

PMID: 30110646
DOI: 10.1016/j.celrep.2018.07.048

Abstract

The clostridium-like ecto-ADP-ribosyltransferase ARTC1 is expressed in a highly restricted manner in skeletal muscle and heart tissue. Although ARTC1 is well studied, the identification of ARTC1 targets in vivo and subsequent characterization of ARTC1-regulated cellular processes on the proteome level have been challenging and only a few ARTC1-ADP-ribosylated targets are known. Applying our recently developed mass spectrometry-based workflow to C2C12 myotubes and to skeletal muscle and heart tissues from wild-type mice, we identify hundreds of ARTC1-ADP-ribosylated proteins whose modifications are absent in the ADP-ribosylome of ARTC1-deficient mice. These proteins are ADP-ribosylated on arginine residues and mainly located on the cell surface or in the extracellular space. They are associated with signal transduction, transmembrane transport, and muscle function. Validation of hemopexin (HPX) as a ARTC1-target protein confirmed the functional importance of ARTC1-mediated extracellular arginine ADP-ribosylation at the systems level.

Keywords: ADP-ribosylation; ARTC1; C2C12; arginine modification; heart; hemopexin; mass spectrometry; muscle; post-translational modification; proteomics.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

ADP Ribose Transferases / chemistry
ADP Ribose Transferases / genetics
ADP Ribose Transferases / metabolism*
ADP-Ribosylation
Animals
Arginine / metabolism
Carrier Proteins / classification
Carrier Proteins / genetics
Carrier Proteins / metabolism
Cell Line
Gene Ontology
Heme / chemistry
Heme / metabolism
Hemopexin / chemistry
Hemopexin / genetics
Hemopexin / metabolism*
Isoenzymes / chemistry
Isoenzymes / genetics
Isoenzymes / metabolism
Male
Membrane Proteins / classification
Membrane Proteins / genetics
Membrane Proteins / metabolism
Mice
Mice, Knockout
Molecular Sequence Annotation
Muscle Fibers, Skeletal / metabolism
Muscle Fibers, Skeletal / pathology
Muscle Proteins / classification
Muscle Proteins / genetics*
Muscle Proteins / metabolism
Muscle Weakness / genetics*
Muscle Weakness / metabolism
Muscle Weakness / pathology
Muscle, Skeletal / metabolism*
Muscle, Skeletal / pathology
Myocardium / metabolism*
Myocardium / pathology
Protein Binding
Protein Processing, Post-Translational*
Proteome / genetics
Proteome / metabolism
Proteomics / methods
Signal Transduction

Substances

Carrier Proteins
Isoenzymes
Membrane Proteins
Muscle Proteins
Proteome
Heme
Hemopexin
Arginine
ADP Ribose Transferases