Targeted truncation of the ADAM17 cytoplasmic domain in mice results in protein destabilization and a hypomorphic phenotype.
ADAM17 (a disintegrin and metalloprotease 17)
TACE (TNFα converting enzyme)
cell surface enzyme
knock-in mutation in mice
membrane protein
myeloid cell
protein stability
Journal
The Journal of biological chemistry
ISSN: 1083-351X
Titre abrégé: J Biol Chem
Pays: United States
ID NLM: 2985121R
Informations de publication
Date de publication:
Historique:
received:
22
11
2020
revised:
21
04
2021
accepted:
28
04
2021
pubmed:
7
5
2021
medline:
1
9
2021
entrez:
6
5
2021
Statut:
ppublish
Résumé
A disintegrin and metalloprotease 17 (ADAM17) is a cell-surface metalloprotease that serves as the principle sheddase for tumor necrosis factor α (TNFα), interleukin-6 receptor (IL-6R), and several ligands of the epidermal growth factor receptor (EGFR), regulating these crucial signaling pathways. ADAM17 activation requires its transmembrane domain, but not its cytoplasmic domain, and little is known about the role of this domain in vivo. To investigate, we used CRISPR-Cas9 to mutate the endogenous Adam17 locus in mice to produce a mutant ADAM17 lacking its cytoplasmic domain (Adam17Δcyto). Homozygous Adam17Δcyto animals were born at a Mendelian ratio and survived into adulthood with slightly wavy hair and curled whiskers, consistent with defects in ADAM17/EGFR signaling. At birth, Adam17Δcyto mice resembled Adam17-/- mice in that they had open eyes and enlarged semilunar heart valves, but they did not have bone growth plate defects. The deletion of the cytoplasmic domain resulted in strongly decreased ADAM17 protein levels in all tissues and cells examined, providing a likely cause for the hypomorphic phenotype. In functional assays, Adam17Δcyto mouse embryonic fibroblasts and bone-marrow-derived macrophages had strongly reduced ADAM17 activity, consistent with the reduced protein levels. Nevertheless, ADAM17Δcyto could be stimulated by PMA, a well-characterized posttranslational activator of ADAM17, corroborating that the cytoplasmic domain of endogenous ADAM17 is not required for its rapid response to PMA. Taken together, these results provide the first evidence that the cytoplasmic domain of ADAM17 plays a pivotal role in vivo in regulating ADAM17 levels and function.
Identifiants
pubmed: 33957124
pii: S0021-9258(21)00522-6
doi: 10.1016/j.jbc.2021.100733
pmc: PMC8191336
pii:
doi:
Substances chimiques
ADAM17 Protein
EC 3.4.24.86
Adam17 protein, mouse
EC 3.4.24.86
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
100733Subventions
Organisme : NIAID NIH HHS
ID : R01 AI079178
Pays : United States
Organisme : NIGMS NIH HHS
ID : F31 GM136144
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA008748
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM008539
Pays : United States
Organisme : NIGMS NIH HHS
ID : R35 GM134907
Pays : United States
Organisme : NIH HHS
ID : S10 OD019986
Pays : United States
Informations de copyright
Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Conflict of interest Drs Maretzky and Blobel hold a patent on a method of identifying agents for combination with inhibitors of iRhoms. Dr Blobel and the Hospital for Special Surgery have identified iRhom2 inhibitors and have cofounded the start-up company SciRhom in Munich to commercialize these inhibitors.
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