The emergence of ADAM10 as a regulator of lymphocyte development and autoimmunity

Abstract

Proteolytic processing of transmembrane receptors and ligands can have a dramatic impact on cell signaling processes and subsequent cellular responses, including activation and differentiation. A member of the disintegrin and metalloproteinase family, ADAM10, has emerged as a prominent regulator of numerous receptors and ligands, including Notch and CD23. Here, we review studies resulting from the recent generation of ADAM10 conditional knockout mice which revealed a critical role for ADAM10 in Notch-dependent lymphocyte development. Additionally, we discuss results of numerous in vitro and ex vivo studies indicating that ADAM10 regulates the production of multiple secreted factors that contribute to autoimmune reactions.

Figure 1. ADAM10-mediated RIP of Notch2 is required for Marginal Zone B cell development

Signaling through the Notch2 receptor expressed on transitional B cells directs marginal zone B cell differentiation(Saito et al., 2003). The Notch2 heterodimer on B cells binds ligands, Jagged 1-2 and Delta-like 1, present on stromal and antigen presenting cells. Binding initiates sequential cleavage events by ADAM10 (S2 cleavage) and a γ-secretase complex (S3 cleavage). Cleavage releases the Notch2 intracellular domain (N2ICD), containing RAM , nuclear localization , transactivating (TAD) , EGF-repeat ,and PEST domains . Transport of the N2ICD to the nucleus followed by binding to the transcription factor, RBP-Jĸ, allows the release of co-repressors (CoR), and attraction of co-activators (CoA) to the transcriptional complex. The activated complex transcribes Notch target genes, including CD21/35, Deltex-1, Hes 1, and Hes 5, that promote development of marginal zone B cells. Deletion of ADAM10, Notch2, and RBP-Jĸ from B cells, or Delta-like 1 from stromal cells prevents marginal zone B cell development.

Figure 2. ADAM10 and Notch similarly regulate B cell development

Precursors to the B cell lineage develop from common lymphoid progenitors (CLPs) in the bone marrow. Constitutive expression of the Notch intracellular domain (NICD), Hes 1 or Hes 5 in CLPs prevents B lineage commitment, while promoting T cell development. Development of the marginal zone B cell (MZB) lineage is regulated by Notch2 signaling. The majority of transitional cells differentiate into follicular B cells, which constitute the majority of circulating B cells. However, ADAM10-mediated Notch2 signaling promotes MZB lineage development. HSC-hematopoietic stem cell, CMP-common myeloid progenitor, Im-Immature. Solid arrows and dashed arrows indicate confirmed and hypothetical differentiation events, respectively.

Figure 3. Ectodomain shedding of CD23, a regulator of IgE-mediated inflammation

CD23 monomers, consisting of a short cytoplasmic tail, a transmembrane portion, an extracellular stalk region forming a coiled-coil structure, and a lectin head domain that binds IgE, form a homo-trimeric tertiary structure, which is stabilized by IgE binding. In the absence of IgE or the presence of anti-stalk antibodies, ADAM10 constitutively cleaves CD23 ectodomains and releases soluble CD23 (sCD23). Cleavage prevents IgE:CD23 interaction at the B cell surface, and results in elevated IgE synthesis. This figure was modified from Conrad et al.(Conrad et al., 2007).