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The CBM signalosome: Potential therapeutic target for aggressive lymphoma?

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Abstract

The CBM signalosome plays a pivotal role in mediating antigen-receptor induced NF-κB signaling to regulate lymphocyte functions. The CBM complex forms filamentous structure and recruits downstream signaling components to activate NF-κB. MALT1, the protease component in the CBM complex, cleaves key proteins in the feedback loop of the NF-κB signaling pathway and enhances NF-κB activation. The aberrant activity of the CBM complex has been linked to aggressive lymphoma. Recent years have witnessed dramatic progresses in understanding the assembly mechanism of the CBM complex, and advances in the development of targeted therapy for aggressive lymphoma. Here, we will highlight these progresses and give an outlook on the potential translation of this knowledge from bench to bedside for aggressive lymphoma patients.

Introduction

NF-κB family of transcription factors plays a critical role in regulating lymphocytes activation, proliferation, survival and effector functions in innate and adaptive immune responses [1], [2]. Defects in NF-κB signaling have been linked to immunodeficiency, and aberrant constitutive activation of NF-κB results in autoimmune diseases or neoplastic disorders [3]. Upon antigen stimulation, the T-cell receptor (TCR) engages MHC-bound antigen peptides and the B-cell receptor (BCR) interacts with antigens, which initiate downstream signaling cascades including activation of a series of kinases, adaptor proteins that culminate in NF-κB activation. Protein kinase C θ (PKCθ) of T-cells and protein kinase β (PKCβ) of B-cells are activated as a part of the antigen-receptor signaling cascade, which further activate their downstream signaling components [1].

The trimolecular protein complex composed of CARMA1 (CARD- and membrane-associated guanylate kinase-like domain-containing protein 1, also called CARD11), Bcl10 (B-cell lymphoma/leukemia 10) and MALT1 (mucosa-associated lymphoid tissue lymphoma translocation protein 1), referred to as the CBM complex, was identified to function downstream of PKCθ/PKCβ and plays a critical role in mediating NF-κB activation in B and T cells upon antigen-receptor stimulation (reviewed in [1], [4]). As a direct target of PKCβ/PKCθ, the CBM complex is activated by PKCβ/PKCθ and recruited to the lipid raft immunological synapse, which subsequently recruits other downstream signaling components such as TRAF2/TRAF6, TAK1 (transforming growth factor-β-activated kinase 1) and TAB (TAK1 binding protein) to activate the inhibitor of nuclear factor-κB (NF-κB) kinase (IKK) complex [1]. In the canonical NF-κB signaling pathway, IKK complex in turn phosphorylates inhibitor of NF-κB (IκB), enables its proteosomal degradation and the release of NF-κB from its sequestration in the cytosol. NF-κB's nuclear localization signal (NLS) is thus exposed, resulting in NF-κB translocation into the nucleus and activation of its target genes [4]. The assembly of the CBM complex also activates the proteolytic activity of paracaspse MALT1, which cleaves and inactivates the negative regulators of NF-κB and further enhances NF-κB activity [5], [6], [7].

Enormous studies have indicated that the genes encoding CARMA1, Bcl10 and MALT1 are bona fide oncogenes. Frequent missense mutations and translocations of these genes have been found in patients with non-Hodgkin's lymphoma [8]. Given the important role that the CBM complex plays in the antigen-receptor signaling pathway as well as other pathways that lead to NF-κB activation, intensive studies have been initiated to delineate the activation mechanisms of CBM in NF-κB signaling. In this review, we will focus on the advances in the structural architecture and assembly mechanism of the CBM complex in the context of antigen-receptor induced NF-κB signaling and progresses in drug discovery research targeting CBM complex as a potential therapeutic target for aggressive lymphomas.

Section snippets

CARMA1

CARMA1 (also known as CARD11 and Bimp3) contains an N-terminal CARD (caspase recruitment domain) domain followed by a long coiled-coil (CC) domain, linker region and a C-terminal MAGUK (membrane-associated guanylate kinase) domain (Fig. 1A). CARD is a subfamily member of death domain (DD) superfamily which usually mediates protein–protein interactions via DD–DD or CARD–CARD interaction between two or more proteins [9], [10]. The CARD domain is the most-studied domain of CARMA1. CARMA1 CARD

The high order assembly of the CBM signalosome

Upon antigen-receptor ligation and signal cascade transduction, CARMA1 CARD is released from the auto-inhibition conformation and becomes accessible for the association with its downstream partners Bcl10 and MALT1 to assemble into the CBM complex, leading to NF-κB activation in T and B cells. CARMA1 interacts with Bcl10 through CARD–CARD interaction and the C-terminus of Bcl10 is responsible for the interaction with the N-terminal Ig domains of MALT1 (Fig. 1A).

Previously, several studies

Functions of the CBM signalosome in mediating NF-κB activation

The CARMA1-Bcl10-MALT1 complex was initially found to function as part of the immune system by mediating the B-cell receptor (BCR) and T-cell receptor (TCR) induced NF-κB activation. CARMA1 is primarily expressed in hematopoietic tissues, while both Bcl10 and MALT1 are expressed in all tissues [13]. In addition to the CARMA1-Bcl10-MALT1 complex that functions in hematopoietic cells, other CARMA family members that have different tissue distribution profiles can also form complexes with Bcl10

Regulation of the CBM signalosome activity

CARMA1, Bcl10 and MALT1 are subject to posttranscriptional regulation to limit the antigen-receptor induced NF-κB signaling and restore homeostasis. As an example, Moreno-Garcia et al. found that phosphorylations of Ser564, Ser657 and Ser649 of CARMA1 have distinct peak profiles as well as different outcomes. Phospho-Ser657 peaked rapidly and declined rapidly after antigen-receptor stimulation, leading to CARMA1-mediated NF-κB activation; however, phosphorylation of Ser649 occurred later but

CBM signalosome and lymphomas

The CBM signalosome serves as the supramolecular hub where it integrates different receptor-induced signaling pathways that lead to NF-κB activation. Its aberrant activation has been associated with many NF-κB signaling dependent lymphocytic neoplasms. For example, CARMA1 overexpression has been found in different lymphocyte malignancies including diffuse large B-cell lymphoma (DLBCL), primary gastric B-cell lymphoma as well as in adult T-cell leukemia [2]. Gain of function mutations of CARMA1

Targeting CBM signalosome for lymphoma

DLBCL is a heterogeneous group of diseases. According to its gene expression profiles, it can be subclassified into three major subtypes: germinal center B cell-like (GCB), activated B cell-like (ABC) and primary mediastinal B cell lymphoma (PMBL) DLBCL. Patients with GCB or PMBL subtype respond relatively well to standard immunochemotherapy and have a better survival rate than patients with ABC subtype. Therefore, ABC-DLBCL subtype is the most clinically challenging subtype and relies on

Conclusions and perspectives

The CBM complex is a key player in NF-κB signaling pathways and it activates NF-κB with two different mechanisms: it provides a central scaffold platform where downstream signaling proteins are recruited to the scaffold and become activated; its enzymatic component MALT1 inactivates the negative feedback loop of NF-κB signaling which further enhances NF-κB activity (Fig. 2). The CBM complex is a nucleation-induced helical filamentous assembly, where CARMA1 acts as the nucleator to promote Bcl10

Acknowledgements

We acknowledge the support from Cancer Research Institute to Q.Q. and L.D. and National Institutes of Health (R01AI089882) to H.W.

Chenghua Yang completed her Ph.D. at Colorado State University in 2009 investigating the structure and function of the MeCP2-nucleosome complex. Between 2009 and 2012, she worked as a postdoctoral associate at Weill Cornell Medical College investigating the assembly mechanism of the CBM complex in NF-κB signaling and developing targeted therapy against the CBM complex for aggressive lymphoma. Then she worked as a Research Scholar at the Memorial Sloan-Kettering Cancer Center investigating the

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    Chenghua Yang completed her Ph.D. at Colorado State University in 2009 investigating the structure and function of the MeCP2-nucleosome complex. Between 2009 and 2012, she worked as a postdoctoral associate at Weill Cornell Medical College investigating the assembly mechanism of the CBM complex in NF-κB signaling and developing targeted therapy against the CBM complex for aggressive lymphoma. Then she worked as a Research Scholar at the Memorial Sloan-Kettering Cancer Center investigating the action mechanism of heat shock protein inhibitors on cancer cells. Now she is transiting to a Professor/Investigator position at the Joint Center for Translational Research of Chronic Diseases in the Institute of Nutritional Science, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Changhai Hospital, The Second Military Medical University in Shanghai. Her research interest focuses on the molecular mechanisms of cancers and the development of targeted therapies against cancers.

    Liron David is a Postdoctoral Research Fellow at Boston Children's Hospital and Harvard Medical School, USA. She completed her Ph.D. at the Technion, Israel Institute of Technology, Israel in 2012 investigating the structure of the Phycobilisome complex, a gigantic light harvesting complex. Since 2012 she has studied the molecular mechanism of the CBM complex in NF-κB signaling.

    Qi Qiao received his B.S. degree of Biotechnology from Peking University in 2006 and Ph.D. degree from Institute of Biophysics, Chinese Academy of Sciences, in 2011. During his Ph.D. training, he worked in the laboratory of Professor Rui-Ming Xu, mainly focused on structural and functional elucidations of histone methyltransferases. In 2012, Dr. Qiao joined Dr. Hao Wu's lab in Weill Cornell Medical Center as a postdoctoral fellow, and later moved to Boston Children's Hospital with the lab. In his postdoc training, he began his studies on the molecular mechanism of signal transduction pathways in both innate and adaptive immune responses, CBM signalosome and activation-induced cytidinedeaminase (AID)related studies respectively. In 2013, Dr. Qiao was awarded the Cancer Research Institute postdoctoral fellowship to support his mechanistic study of AID in immunity and cancer.

    Ermelinda Damko is a Lab Supervisor in the laboratory of Professor Frederick Maxfield at Weill Cornell Medical College since 2012. She received her MS degree from Columbia University in 2008. Between 2008 and 2012 she worked as a Research Specialist at the Professor Hao Wu's lab at Weill Cornell Medical College.

    Hao Wu is Asa and Patricia Springer Professor of Pediatrics and of Biological Chemistry and Molecular Pharmacology at Harvard Medical School, and Senior Investigator in the Program in Cellular and Molecular Medicine at Boston Children's Hospital. She completed her Ph.D. with Dr. Michael Rossmann at Purdue University in 1992 and worked as a Postdoctoral Fellow in the laboratory of Professor Wayne Hendrickson at Columbia University between 1992 and 1997. She became an Assistant Professor at Weill Cornell Medical College in 1997 and was promoted to Professor in 2003. In 2012, she moved to Harvard Medical School. Her lab focuses on elucidating the molecular mechanism of signal transduction by immune receptors, especially innate immune receptors.

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