BAFF- and TACI-Dependent Processing of BAFFR by ADAM Proteases Regulates the Survival of B Cells

Smulski, Cristian R.; Küry, Patrick; Seidel, L.; Staiger, Harald; Edinger, Anna K.; Willen, Laure; Seidl, Maximilian; Hess, Henry; Salzer, Ulrich; Rolink, Antonius; Rizzi, Marta; Schneider, Pascal; Eibel, Hermann

doi:10.1016/j.celrep.2017.02.005

Cited by 68 publications

(70 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…One prominent example is the soluble tissue inhibitors of metalloproteases that (to various extent) block ADAM10, ADAM17, and MT‐MMPs (e.g., Amour et al , , ). Conversely, other ligands are known to induce shedding as observed for Notch, RGMa, BAFFR, and DDR1 (Pan & Rubin, ; Bozkulak & Weinmaster, ; van Tetering et al , ; van Erp et al , ; Shitomi et al , ; Smulski et al , ). An emerging layer of regulation is post‐translational modification at the substrate level.…”

Section: Regulation Of Sheddingmentioning

confidence: 99%

Proteolytic ectodomain shedding of membrane proteins in mammals—hardware, concepts, and recent developments

2018

View full text Add to dashboard Cite

Proteolytic removal of membrane protein ectodomains (ectodomain shedding) is a post-translational modification that controls levels and function of hundreds of membrane proteins. The contributing proteases, referred to as sheddases, act as important molecular switches in processes ranging from signaling to cell adhesion. When deregulated, ectodomain shedding is linked to pathologies such as inflammation and Alzheimer's disease. While proteases of the "a disintegrin and metalloprotease" (ADAM) and "beta-site APP cleaving enzyme" (BACE) families are widely considered as sheddases, in recent years a much broader range of proteases, including intramembrane and soluble proteases, were shown to catalyze similar cleavage reactions. This review demonstrates that shedding is a fundamental process in cell biology and discusses the current understanding of sheddases and their substrates, molecular mechanisms and cellular localizations, as well as physiological functions of protein ectodomain shedding. Moreover, we provide an operational definition of shedding and highlight recent conceptual advances in the field. While new developments in proteomics facilitate substrate discovery, we expect that shedding is not a rare exception, but rather the rule for many membrane proteins, and that many more interesting shedding functions await discovery.

show abstract

Section: Regulation Of Sheddingmentioning

confidence: 99%

Proteolytic ectodomain shedding of membrane proteins in mammals—hardware, concepts, and recent developments

2018

View full text Add to dashboard Cite

show abstract

“…Each receptor exhibits a unique expression pattern on distinct B cell subsets, in part accounting for differential functional roles during an immune response. 28 29). 25 All three of the BAFF/APRIL receptors can be shed from the cell surface by the activity of γ-secretase (BCMA) or ADAM proteases (BAFF-R and TACI).…”

Section: Baff Family Receptorsmentioning

confidence: 99%

“…28 and Jnk/p38 pathways to counteract apoptosis, drive immunoglobulin class switch recombination, and promote antibody production. 28 and Jnk/p38 pathways to counteract apoptosis, drive immunoglobulin class switch recombination, and promote antibody production.…”

Section: Baff Family Receptorsmentioning

confidence: 99%

“…[91][92][93] Moreover, a subset of autoantibody specificities can persist despite anti-CD20 B cell depletion, implicating GC-derived CD20 neg long-lived plasma cells in their genesis. 28 Despite these data, Baff -/mice exhibit a defect in the formation of a mature follicular dendritic cell (FDC) network and are characterized by premature GC termination. 94 Based on these observations, the contribution of BAFF signals to autoreactive GC formation is particularly relevant.…”

Section: Distinct Contribution Of Ef and Gc Pathways To Lupus Pathomentioning

confidence: 99%

See 1 more Smart Citation

BAFF inhibition in SLE—Is tolerance restored?

Jackson

Davidson

2019

Immunological Reviews

View full text Add to dashboard Cite

The B cell activating factor (BAFF) inhibitor, belimumab, is the first biologic drug approved for the treatment of SLE, and exhibits modest, but durable, efficacy in decreasing disease flares and organ damage. BAFF and its homolog APRIL are TNF‐like cytokines that support the survival and differentiation of B cells at distinct developmental stages. BAFF is a crucial survival factor for transitional and mature B cells that acts as rheostat for the maturation of low‐affinity autoreactive cells. In addition, BAFF augments innate B cell responses via complex interactions with the B cell receptor (BCR) and Toll like receptor (TLR) pathways. In this manner, BAFF impacts autoreactive B cell activation via extrafollicular pathways and fine tunes affinity selection within germinal centers (GC). Finally, BAFF and APRIL support plasma cell survival, with differential impacts on IgM‐ and IgG‐producing populations. Therapeutically, BAFF and combined BAFF/APRIL inhibition delays disease onset in diverse murine lupus strains, although responsiveness to BAFF inhibition is model dependent, in keeping with heterogeneity in clinical responses to belimumab treatment in humans. In this review, we discuss the mechanisms whereby BAFF/APRIL signals promote autoreactive B cell activation, discuss whether altered selection accounts for therapeutic benefits of BAFF inhibition, and address whether new insights into BAFF/APRIL family complexity can be exploited to improve human lupus treatments.

show abstract

“…1A). Smulski et al recently reported that unlike TACI and BCMA, BAFF-R is not constitutively shed, and processing requires BAFF stimulation and TACI coexpression (45). Stimulation with a homotrimeric BAFF 3-mer, which triggers BAFF-R but not TACI (46), activates ADAM10 to cleave and release BAFF-R from the membrane in the presence of TACI.…”

Section: Introductionmentioning

confidence: 99%

The Role of BAFF System Molecules in Host Response to Pathogens

Sakai

Akkoyunlu

2017

Clin Microbiol Rev

View full text Add to dashboard Cite

The two ligands B cell-activating factor of the tumor necrosis factor family (BAFF) and a proliferation-inducing ligand (APRIL) and the three receptors BAFF receptor (BAFF-R), transmembrane activator and calcium-modulating cyclophilin ligand interactor (TACI), and B cell maturation antigen (BCMA) are members of the "BAFF system molecules." BAFF system molecules are primarily involved in B cell homeostasis. The relevance of BAFF system molecules in host responses to microbial assaults has been investigated in clinical studies and in mice deficient for each of these molecules. Many microbial products modulate the expression of these molecules. Data from clinical studies suggest a correlation between increased expression levels of BAFF system molecules and elevated B cell responses. Depending on the pathogen, heightened B cell responses may strengthen the host response or promote susceptibility. Whereas pathogen-mediated increases in the expression levels of the ligands and/or the receptors appear to promote microbial clearance, certain pathogens have evolved to ablate B cell responses by suppressing the expression of TACI and/or BAFF-R on B cells. Other than its well-established role in B cell responses, the TACI-mediated activation of macrophages is also implicated in resistance to intracellular pathogens. An improved understanding of the role that BAFF system molecules play in infection may assist in devising novel strategies for vaccine development.

show abstract

BAFF- and TACI-Dependent Processing of BAFFR by ADAM Proteases Regulates the Survival of B Cells

Cited by 68 publications

References 52 publications

Proteolytic ectodomain shedding of membrane proteins in mammals—hardware, concepts, and recent developments

Proteolytic ectodomain shedding of membrane proteins in mammals—hardware, concepts, and recent developments

BAFF inhibition in SLE—Is tolerance restored?

The Role of BAFF System Molecules in Host Response to Pathogens

Contact Info

Product

Resources

About