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The emerging role of ADAM metalloproteinases in immunity

Nature Reviews Immunology volume 18, pages 745–758 (2018)Cite this article

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Abstract

Proteolysis is an irreversible physiological process that can result in the termination or activation of protein function. Many transmembrane proteins that are involved in the cellular communication between immune cells and structural cells — for example, Notch, CD23, CD44, and membrane-anchored cytokines and their receptors — are cleaved by the ADAM (a disintegrin and metalloproteinase) family of enzymes. Here, we review recent insights into the molecular activation, substrate specificity and function of ADAM proteins in the development and regulation of the immune system, with a particular focus on the roles of ADAM10 and ADAM17.

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Fig. 1: Structure of human proteolytically active ADAM and ADAMTS proteins.
Fig. 2: Regulation of ADAM proteins.
Fig. 3: Notch activation by ADAM proteins.
Fig. 4: Role of ADAM10 in T cells.
Fig. 5: Role of ADAM10 in marginal zone B cell development.

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Acknowledgments

Reviewer information

Nature Reviews Immunology thanks D. Conrad, M. Tomlinson and the other, anonymous reviewer(s) for their contribution to the peer review of this work.

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Authors and Affiliations

  1. VIB Center for Inflammation Research, Ghent University, Ghent, Belgium

    Bart N. Lambrecht, Matthias Vanderkerken & Hamida Hammad

  2. Department of Respiratory Medicine, University Hospital Ghent, Ghent, Belgium

    Bart N. Lambrecht & Hamida Hammad

  3. Department of Pulmonary Medicine, ErasmusMC, Rotterdam, Netherlands

    Bart N. Lambrecht

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Supplementary information

Glossary

γ-Secretases

Large proteinase complexes that cleave substrates within their transmembrane domain.

Tetraspanins

A superfamily of widely expressed membrane proteins involved in membrane compartmentalization.

Rhomboid proteins

An evolutionarily conserved family of intramembrane serine proteases implicated in diverse cellular functions.

Thymic epithelial cells

(TECs). Antigen-presenting cells in the thymus that regulate the T cell repertoire and establish central tolerance.

Autoimmune regulator protein

(AIRE). A transcription factor expressed in the thymic medulla that drives negative selection of self-recognizing T cells.

T cell exhaustion

A state of T cell dysfunction arising during chronic infections and cancer.

Activation-induced cell death

Programmed cell death owing to FAS–FAS ligand (FASL) interactions.

Indoleamine 2-3-dioxygenase pathway

(IDO pathway). A pathway mediating immunosuppressive effects through the metabolism of tryptophan to kynurenine.

Type 1 immune responses

Immune responses against intracellular microorganisms characterized by the involvement of group 1 innate lymphoid cells, CD8+ cytotoxic T cells and CD4+ T helper 1 cells.

Somatic hypermutation

Enzymatic modification of immunoglobulin genes required for the generation of high-affinity antibodies.

Marginal zone reticular cells

(MRCs). A stromal cell type in secondary lymphoid tissues, primarily located in the outer edge of follicles.

Capping regions

Areas of surface cell membrane in B cells containing clusters of crosslinked B cell receptors.

Airway remodelling

Structural changes in the large and small airways that occur in various diseases such as asthma.

Innate lymphoid cells

(ILCs). Immune cells that belong to the lymphoid lineage but do not express antigen-specific receptors.

Antibody-dependent cytotoxicity

A mechanism through which crystallizable fragment (Fc) receptor-bearing effector cells can recognize and kill antibody-coated target cells.

IL-6R trans-signalling

The activation of membrane-bound gp130 by a complex of IL-6 with the soluble IL-6 receptor.

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Lambrecht, B.N., Vanderkerken, M. & Hammad, H. The emerging role of ADAM metalloproteinases in immunity. Nat Rev Immunol 18, 745–758 (2018). https://doi.org/10.1038/s41577-018-0068-5

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