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Cited by 13Protease and Inhibitor MechanismsDevelopmental Biology and Gene RegulationNeurobiology and Insect Physiology Research

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An unexpected role for the conserved ADAM-family metalloprotease ADM-2 in Caenorhabditis elegans molting

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Joseph, Braveen B., Edeen, Phillip T., Meadows, Sarina, Binti, Shaonil, Fay, David S.·2022·PLOS Genetics
DOI 10.1371/journal.pgen.1010249PMC PMC9187072

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Abstract

Molting is a widespread developmental process in which the external extracellular matrix (ECM), the cuticle, is remodeled to allow for organismal growth and environmental adaptation. Studies in the nematode Caenorhabditis elegans have identified a diverse set of molting-associated factors including signaling molecules, intracellular trafficking regulators, ECM components, and ECM-modifying enzymes such as matrix metalloproteases. C . elegans NEKL-2 and NEKL-3, two conserved members of the NEK family of protein kinases, are essential for molting and promote the endocytosis of environmental steroid-hormone precursors by the epidermis. Steroids in turn drive the cyclic induction of many genes required for molting. Here we report a role for the sole C . elegans ADAM–meltrin metalloprotease family member, ADM-2, as a mediator of molting. Loss of adm-2 , including mutations that disrupt the metalloprotease domain, led to the strong suppression of molting defects in partial loss-of-function nekl mutants. ADM-2 is expressed in the epidermis, and its trafficking through the endo-lysosomal network was disrupted after NEKL depletion. We identified the epidermally expressed low-density lipoprotein receptor–related protein, LRP-1, as a candidate target of ADM-2 regulation. Whereas loss of ADM-2 activity led to the upregulation of apical epidermal LRP-1, ADM-2 overexpression caused a reduction in LRP-1 levels. Consistent with this, several mammalian ADAMs, including the meltrin ADAM12, have been shown to regulate mammalian LRP1 via proteolysis. In contrast to mammalian homologs, however, the regulation of LRP-1 by ADM-2 does not appear to involve the metalloprotease function of ADM-2, nor is proteolytic processing of LRP-1 strongly affected in adm-2 mutants. Our findings suggest a noncanonical role for an ADAM family member in the regulation of a lipoprotein-like receptor and lead us to propose that endocytic trafficking may be important for both the internalization of factors that promote molting as well as the removal of proteins that can inhibit the process.

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Metadata

Authors
Joseph, B. B., Edeen, P. T., Meadows, S., Binti, S., & Fay, D. S.
Affiliations
University of Wyoming (US)
Corresponding author
Fay, David S.
ORCID
Venue
PLOS Genetics
Publisher
Public Library of Science (PLoS)
Published
2022-05-31
Volume
18
Issue
5
Pages
e1010249
ISSN
  • 1553-7390 (ISSN-L)
  • 1553-7404
DOI
10.1371/journal.pgen.1010249
PMC
PMC9187072
OpenAlex
W4282946166
Cited by
13
References
1
Citations by year
2026: 1 · 2025: 4 · 2024: 5 · 2023: 2 · 2022: 1
FWCI
1.26
Type
journal article
Language
en
Update notices
new_version (2022-06-10)
Open access
Licence
Locations
  • PLoS Genetics (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, public-domain)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
Foundation for the National Institutes of Health (GM136236, P20GM103432)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurobiology and Insect Physiology Research
Keywords
ADAM metalloproteases, molting, Caenorhabditis elegans, LRP1, low density lipoprotein receptor-related protein, epidermis, endosomal trafficking, extracellular matrix, protein internalization
MeSH terms
Animals, Endocytosis, Mammals, Caenorhabditis elegans, Molting, Caenorhabditis elegans Proteins, Metalloproteases

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