Differential requirement of MALT1 for BAFF-induced outcomes in B cell subsets

Tusche, Michael W.; Ward, Lesley A.; Vu, Frances; McCarthy, Doug; Quintela‐Fandino, Miguel; Ruland, Jürgen; Gommerman, Jennifer L.; Mak, Tak W.

doi:10.1084/jem.20091802

Cited by 57 publications

(48 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition, our data that identify leptin as a B cell survival factor that protects B cells from apoptosis and induces cell cycle entry similar to the function of BAFF (20). B cell development depends critically on BAFF, which initiates signaling and transcriptional programs including activation of Akt and NF-KB pathways and induction of antiapoptotic members of the Bcl-2 family as well as cyclin D1 and D2 expression (20,21). Although there are similar properties between leptin and BAFF signaling, whereas db/db B cells express normal level of BAFF receptor, they are not as responsive to BAFF stimulation as WT control, suggesting the possibility of the two cytokines sharing both common as well as nonredundant pathways (Fig.…”

Section: Discussionmentioning

confidence: 58%

“…Our findings that leptin activates Akt, STAT3, and NF-KB pathways are consistent with the link of these signaling molecules to Bcl-2 and cyclin D1 expression. In addition, our data that identify leptin as a B cell survival factor that protects B cells from apoptosis and induces cell cycle entry similar to the function of BAFF (20). B cell development depends critically on BAFF, which initiates signaling and transcriptional programs including activation of Akt and NF-KB pathways and induction of antiapoptotic members of the Bcl-2 family as well as cyclin D1 and D2 expression (20,21).…”

Section: Discussionmentioning

confidence: 66%

See 1 more Smart Citation

Leptin signaling maintains B-cell homeostasis via induction of Bcl-2 and Cyclin D1

Lam

Wang

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Regulation of apoptosis and cell cycle progression plays an essential role in the maintenance of B-cell homeostasis, because a fine balance of survival and expansion is critical for preventing lymphocytic disorders. Although remarkable progress in understanding B-cell development has been achieved, much less is known concerning niches that are critical to the maintenance of B-cell homeostasis. Leptin has recently been recognized to be important for modulating the immune responses, but it has remained unclear how leptin signaling influences B-cell physiology. A variety of lymphocytic malignancies have been reported to be linked to leptin, and therefore it is necessary to elucidate the mechanisms involved. Here we demonstrate that leptin promotes B-cell homeostasis by inhibiting apoptosis and by inducing cell cycle entry through the activation of expressions of B-cell CLL/lymphoma 2 (Bcl-2) and cyclin D1. We further show that leptin can induce Bcl-2 and cyclin D1 expression by two pathways, including the direct activation of their promoters and suppression of microRNAs (miRNAs) that target their putative 3′untranslated regions. Amplification of these leptin-modulated miRNAs inhibited B lymphoma cell growth. These findings provide insights into mechanisms for leptin regulation of the humoral immune system and suggest new therapeutic strategies for leptin receptor expressing malignancies.B cell survival | apoptosis | proliferation | microRNA A poptosis plays an essential role in the maintenance of B-cell homeostasis, a process that is regulated by a fine balance between the continual generation of new B lymphocytes and their elimination through multiple checkpoints in both bone marrow (BM) and secondary lymphoid organs (1). The balance between B cell survival and death is critical because excessive apoptosis may lead to immunodeficiencies whereas insufficient apoptosis may result in autoimmunity and even lymphoid malignancies (2). B cells that are optimally activated escape apoptosis and transit through different cell cycle checkpoints. B-cell CLL/lymphoma 2 (Bcl-2) family proteins, which function to preserve or disturb mitochondrial integrity, are required for the maintenance of immune homeostasis (2, 3). Targeted loss of the antiapoptotic member gene Bcl-2 has led to massive apoptosis of lymphocytes, whereas overexpression of Bcl-2 has caused the accumulation of B cells (4, 5). D-type cyclins are key players in the G 1 checkpoint control mechanism and are critical for cell proliferation (6). Both Bcl-2 and D-type cyclins are prime targets for novel therapeutics because their overexpression is common in many hematological diseases and many types of cancers (7,8). MicroRNAs (miRNAs) are increasingly recognized for their prominent role in immune homeostasis, while the accumulating evidence for aberrant miRNA expression in B-cell-derived tumors underscores miRNAs as potential targets for cancer therapeutics (9). Therefore, elucidation of the regulatory mechanisms of miRNAs in peripheral B cells will contribute to a fu...

show abstract

Section: Discussionmentioning

confidence: 58%

Section: Discussionmentioning

confidence: 66%

Leptin signaling maintains B-cell homeostasis via induction of Bcl-2 and Cyclin D1

Lam

Wang

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…Unlike its essential role in TCR signaling, MALT1 is largely dispensable for canonical NF-κB activation by BCR [84]. Interestingly, MALT1 has recently been shown to regulate BAFFR-mediated p100 processing in B cells [85]. MALT1 physically interacts with TRAF3 and appears to induce degradation of this negative regulator of NIK.…”

Section: Nik Regulatorsmentioning

confidence: 99%

Non-canonical NF-κB signaling pathway

2010

View full text Add to dashboard Cite

The non-canonical NF-κB pathway is an important arm of NF-κB signaling that predominantly targets activation of the p52/RelB NF-κB complex. This pathway depends on the inducible processing of p100, a molecule functioning as both the precursor of p52 and a RelB-specific inhibitor. A central signaling component of the non-canonical pathway is NF-κB-inducing kinase (NIK), which integrates signals from a subset of TNF receptor family members and activates a downstream kinase, IκB kinase-α (IKKα), for triggering p100 phosphorylation and processing. A unique mechanism of NIK regulation is through its fate control: the basal level of NIK is kept low by a TRAF-cIAP destruction complex and signal-induced non-canonical NF-κB signaling involves NIK stabilization. Tight control of the fate of NIK is important, since deregulated NIK accumulation is associated with lymphoid malignancies.

show abstract

“…Our previous [79]. Although there is no report implicating a role of CARMA1 or Bcl10 in the noncanonical pathway, one study suggests that MALT1 may be required for BAFF receptor-induced p100 processing [80].…”

Section: The Mechanism Of T Cell Receptor-induced Car-ma1 Activationmentioning

confidence: 99%

NF-κB signaling pathways regulated by CARMA family of scaffold proteins

Blonska¹,

Lin²

2010

Cell Res

176

201

View full text Add to dashboard Cite

The NF-κB family of transcription factors plays a crucial role in cell activation, survival and proliferation. Its aberrant activity results in cancer, immunodeficiency or autoimmune disorders. Over the past two decades, tremendous progress has been made in our understanding of the signals that regulate NF-κB activation, especially how scaffold proteins link different receptors to the NF-κB-activating complex, the IκB kinase complex. The growing number of these scaffolds underscores the complexity of the signaling networks in different cell types. In this review, we discuss the role of scaffold molecules in signaling cascades induced by stimulation of antigen receptors, G-protein-coupled receptors and C-type Lectin receptors, resulting in NF-κB activation. Especially, we focus on the family of Caspase recruitment domain (CARD)-containing proteins known as CARMA and their function in activation of NF-κB, as well as the link of these scaffolds to the development of various neoplastic diseases through regulation of NF-κB.

show abstract

Differential requirement of MALT1 for BAFF-induced outcomes in B cell subsets

Cited by 57 publications

References 45 publications

Leptin signaling maintains B-cell homeostasis via induction of Bcl-2 and Cyclin D1

Leptin signaling maintains B-cell homeostasis via induction of Bcl-2 and Cyclin D1

Non-canonical NF-κB signaling pathway

NF-κB signaling pathways regulated by CARMA family of scaffold proteins

Contact Info

Product

Resources

About