N-WASP Is Essential for the Negative Regulation of B Cell Receptor Signaling

Liu, Chaohong; Bai, Xu; Wu, Junfeng; Sharma, Satendra; Upadhyaya, Arpita; Dahlberg, Carin; Westerberg, Lisa S.; Snapper, Scott B.; Zhao, Xiaodong; Song, Wenxia

doi:10.1371/journal.pbio.1001704

Cited by 73 publications

(151 citation statements)

References 73 publications

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“…WiskottAldrich syndrome protein (WASP) and neural WASP (N-WASP) were reported as direct binding targets of mycolactone [7,21]. These proteins are members of a family of scaffold proteins transducing signals involved in the dynamic remodeling of the actin cytoskeleton [22][23][24][25]. Mycolactone exerts its effects by hijacking the WASP family, leading to uncontrolled activation of actin in the cytoplasm [21].…”

Section: Discussionmentioning

confidence: 99%

Suppressive effect of mycolactone-containing fraction from Mycobacterium ulcerans on antibody production against co-administered antigens

Shinoda¹,

Nakamura²,

Watanabe³

2017

Biomed Res Clin Prac

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Mycobacterium ulcerans infection causes Buruli ulcer, a chronic and destructive necrotizing skin ulcer in humans. The symptoms of Buruli ulcer are mainly caused by unique toxic macrolides, named mycolactone. The suppression of Th 1 -type immune responses and inflammatory responses is caused by mycolactone in humans and animal models. However, the effects of mycolactone on serum immune responses remain unclear. In this study, we administered model antigens with partially purified mycolactone into mice to examine its effect on antibody production in serum. Mycolactone-containing fraction suppressed antibody production against co-administered antigens in a dose-dependent manner. The suppressive effect was not observed when the antigens and mycolactone preparation were injected into different sites. Additionally, the effect was demonstrated only against co-administered antigens. Moreover, mycolactone-containing fraction was considered safe even at doses ten times higher than the dose that suppressed the antibody responses, suggesting potential usefulness of mycolactone as a new immunoregulatory agent to specifically prevent antibody response against co-administered antigens.

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Section: Discussionmentioning

confidence: 99%

Suppressive effect of mycolactone-containing fraction from Mycobacterium ulcerans on antibody production against co-administered antigens

Shinoda¹,

Nakamura²,

Watanabe³

2017

Biomed Res Clin Prac

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“…Loss of WAS in mouse B cells leads to reduction of filamentous actin in resting B cells and impairs the development, adhesion and migration of B cells in the periphery (Table 1) 8,34 . In response to antigen, WASdeficient B cells have reduced BCR internalization and increased signalling and antibody production 7,35 , resembling the B cell phenotype in patients with WiskottAldrich syndrome. Loss of WASL also increases B cell responsiveness to antigens 35 .…”

Section: [H1] Structure Of the Cortical Cytoskeletonmentioning

confidence: 98%

“…In response to antigen, WASdeficient B cells have reduced BCR internalization and increased signalling and antibody production 7,35 , resembling the B cell phenotype in patients with WiskottAldrich syndrome. Loss of WASL also increases B cell responsiveness to antigens 35 .…”

Section: [H1] Structure Of the Cortical Cytoskeletonmentioning

confidence: 98%

“…Surprisingly, while the absence of WAS reduces the amount of cortical actin and impairs the structure of immune synapses 7,34,35 , the absence of WASL increases the amount of actin in B cell synapses 35 , suggesting that their role in actin polymerization is also distinct.…”

Section: [H1] Structure Of the Cortical Cytoskeletonmentioning

confidence: 99%

“…This is similar to the endocytosis of soluble antigen, which also requires CCPs 124 . The endocytosis of antigen depends on SRC-family kinases 125 , BTK 126 , activation of the ARP2/3 complex through WAS, WASL, and WIPF1 7,35,60 and linkage of CCPs to actin by DBNL 127 . However, the endocytic mechanism may not be identical to that involving canonical CCPs as it requires RAC1 and RAC2, but not the typical regulator of actin polymerization in CCPs, CDC42 50 .…”

Section: [H1] Cytoskeletal Regulation Of Bcr Signallingmentioning

confidence: 99%

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Cytoskeletal control of B cell responses to antigens

Tolar

2017

Nat Rev Immunol

125

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The actin cytoskeleton is essential for cell mechanics and has increasingly been implicated in the regulation of cell signalling. In B cells, the actin cytoskeleton couples extensively to B cell receptor (BCR) signalling pathways and its defects can either enhance or suppress B cell activation. Recent insights from single-cell imaging and biophysical techniques suggest that actin orchestrates BCR signalling at the plasma membrane through effects on protein diffusion, and that it regulates antigen discrimination through the biomechanics of immune synapses. These mechanical functions also play a role in the adaptation of B cell subsets to specialized tasks during antibody responses.3

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Wiskott‐Aldrich syndrome protein: Emerging mechanisms in immunity

Rivers

Thrasher

2017

Eur J Immunol

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The Wiskott-Aldrich syndrome protein (WASP) participates in innate and adaptive immunity through regulation of actin cytoskeleton-dependent cellular processes, including immune synapse formation, cell signaling, migration and cytokine release. There is also emerging evidence for a direct role in nuclear transcription programmes uncoupled from actin polymerization. A deeper understanding of some of the more complex features of Wiskott Aldrich syndrome (WAS) itself, such as the associated autoimmunity and inflammation, has come from identification of defects in the number and function of anti-inflammatory myeloid cells and regulatory T and B cells, as well as defects in positive and negative B-cell selection. In this review we outline the cellular defects that have been characterized in both human WAS patients and murine models of the disease. We will emphasize in particular recent discoveries that provide a mechanistic insight into disease pathology, including lymphoid and myeloid cell homeostasis, immune synapse assembly and immune cell signaling.

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N-WASP Is Essential for the Negative Regulation of B Cell Receptor Signaling

Abstract: A cell biology study using conditional gene knockout mouse models reveals a novel mechanism by which the actin cytoskeleton negatively regulates the signal transduction of the B cell antigen receptor.

Cited by 73 publications

References 73 publications

Suppressive effect of mycolactone-containing fraction from Mycobacterium ulcerans on antibody production against co-administered antigens

Suppressive effect of mycolactone-containing fraction from Mycobacterium ulcerans on antibody production against co-administered antigens

Cytoskeletal control of B cell responses to antigens

Wiskott‐Aldrich syndrome protein: Emerging mechanisms in immunity

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