title: Secreted VAPB/ALS8 major sperm protein domains modulate mitochondrial localization and morphology via growth cone guidance receptors.
abstract: The VAPB/ALS8 major sperm protein domain (vMSP) is implicated in amyotrophic lateral sclerosis and spinal muscular atrophy, yet its function in the nervous system is not well understood. In Caenorhabditis elegans and Drosophila, the vMSP is cleaved from its transmembrane anchor and secreted in a cell type-specific fashion. We show that vMSPs secreted by neurons act on Lar-like protein-tyrosine phosphatase and Roundabout growth cone guidance receptors expressed in striated muscle. This signaling pathway promotes Arp2/3-dependent actin remodeling and mitochondrial localization to actin-rich muscle I-bands. C. elegans VAPB mutants have mitochondrial localization, morphology, mobility, and fission/fusion defects that are suppressed by Lar-like receptor or Arp2/3 inactivation. Hence, growth cone guidance receptor pathways that remodel the actin cytoskeleton have unanticipated effects on mitochondrial dynamics. We propose that neurons secrete vMSPs to promote striated muscle energy production and metabolism, in part through the regulation of mitochondrial localization and function.
authors.affiliation: Department of Cell Biology, University of Alabama School of Medicine, Birmingham, AL 35294, USA.
authors.forename: Sung Min
authors.initials: SM
authors.lastname: Han
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Tsuda
authors.forename: Youfeng
authors.initials: Y
authors.lastname: Yang
authors.forename: Jack
authors.initials: J
authors.lastname: Vibbert
authors.forename: Pauline
authors.initials: P
authors.lastname: Cottee
authors.forename: Se-Jin
authors.initials: SJ
authors.lastname: Lee
authors.forename: Jessica
authors.initials: J
authors.lastname: Winek
authors.forename: Claire
authors.initials: C
authors.lastname: Haueter
authors.forename: Hugo J
authors.initials: HJ
authors.lastname: Bellen
authors.forename: Michael A
authors.initials: MA
authors.lastname: Miller
mesh_terms: D051376:Actin-Related Protein 2-3 Complex / Q000378:metabolism; D000199:Actins / Q000378:metabolism; D000818:Animals; D030801:Animals, Genetically Modified; D017173:Caenorhabditis elegans / Q000235:genetics / Q000254:growth & development / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D005453:Fluorescence; D020439:Growth Cones / Q000378:metabolism*; D015801:Helminth Proteins / Q000235:genetics / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D054792:Muscle, Striated / Q000166:cytology / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D019076:Transgenes / Q000502:physiology
chemical_list: D051376:Actin-Related Protein 2-3 Complex; D000199:Actins; D029742:Caenorhabditis elegans Proteins; D015801:Helminth Proteins; C050602:major sperm protein, nematode