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Substrate-selective protein ectodomain shedding by ADAM17 and iRhom2 depends on their juxtamembrane and transmembrane

Beiyu Tang1,2, Xue Li1,3, Thorsten Maretzky4

  • 1Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, New York, NY, USA.

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology
|February 28, 2020
PubMed

Insights

The metalloprotease ADAM17 (a disintegrin and metalloprotease 17) requires iRhom2 for activation, and its juxtamembrane domains regulate substrate selectivity, impacting conditions like Tetralogy of Fallot.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Background:

  • ADAM17 (a disintegrin and metalloprotease 17) is a key regulator of EGF-receptor and TNFα signaling, crucial for barrier integrity and implicated in autoimmunity.
  • ADAM17 activation is linked to its transmembrane domain (TMD) and potential partners like inactive Rhomboids (iRhoms).
  • Alternative models for ADAM17 regulation exist, independent of iRhoms.

Purpose of the Study:

  • To investigate the role of iRhoms in ADAM17 activation and regulation.
  • To explore the function of juxtamembrane domains (JMDs) in ADAM17 substrate selectivity.
  • To examine the impact of ADAM17 mutations on specific signaling pathways and developmental processes.

Main Methods:

  • Utilized a non-activatable ADAM17 mutant with a betacellulin (BTC) TMD.
  • Employed knockout cell lines (Adam17-/- and iRhom1/2-/-) to assess iRhom dependency.
  • Analyzed the effects of mutations in ADAM17 and iRhom2 JMDs on ADAM17 activity and substrate preference.

Main Results:

  • ADAM17 activation by its TMD is dependent on the presence of iRhoms.
  • The extracellular JMDs of ADAM17 and iRhom2 were shown to regulate ADAM17 stimulation and substrate selectivity.
  • A patient-derived mutation in the ADAM17 JMD altered its selectivity towards HB-EGF, a critical factor in heart valve development.

Conclusions:

  • ADAM17 activation is critically dependent on an interaction with iRhom2.
  • The JMDs of ADAM17 and iRhom2 play essential roles in modulating ADAM17 function and substrate targeting.
  • Findings provide insights into ADAM17 regulation and its link to congenital heart defects like Tetralogy of Fallot.
Keywords:
ADAM17 (a disintegrin and metalloprotease 17)EGFR (epidermal growth factor receptor)Rhbdf1/2 (rhomboid family member 1/2)TGFα (transforming growth factor α)TNFα (tumor necrosis factor α)iRhom1/2 (inactive Rhomboid like protein 1/2)

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