Molecular architecture and regulation of BCL10-MALT1 filaments

Schlauderer, Florian; Seeholzer, Thomas; Desfosses, Ambroise; Gehring, Torben; Strauß, Michael; Hopfner, Karl‐Peter; Gutsche, Irina; Krappmann, Daniel; Lammens, Katja

doi:10.1038/s41467-018-06573-8

Cited by 56 publications

(82 citation statements)

References 63 publications

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“…The large molecular complexes formed by the helical assembly of DD superfamily members were difficult to determine by their crystal structure because it is impossible to crystallize a helical structure unless the helical periodicity happens to be an integer. With the development of advanced cryo-electron microscopy (EM) technology, many helical filament structures of the DD superfamily, important for SMOC formation, have been determined 18,19,21,[46][47][48][49][50] . These structural studies revealed that members of the DD superfamily use a common assembly mechanism, detected during the structural study of the RAIDD DD/PIDD DD complex, to form the helical filament structure in SMOCs.…”

Section: Smoc Formation By the Dd Superfamilymentioning

confidence: 99%

Assembly of platforms for signal transduction in the new era: dimerization, helical filament assembly, and beyond

Chun

Park

2020

Exp Mol Med

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Supramolecular organizing center (SMOC)-mediated signal transduction is an emerging concept in the field of signal transduction that is ushering in a new era. The formation of location-specific, higher-order SMOCs is particularly important for cell death and innate immune signaling processes. Several protein interaction domains, including the death domain (DD) superfamily and the CIDE domain, are representative mediators of SMOC assembly in cell death and innate immune signaling pathways. DD superfamily-and CIDE domain-containing proteins form SMOCs that activate various caspases and provide signaling scaffold platforms. These assemblies can lead to signal transduction and amplification during signaling events. In this review, we summarize recent findings on the molecular basis of DD superfamily-and CIDE domain-mediated SMOC formation.

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Section: Smoc Formation By the Dd Superfamilymentioning

confidence: 99%

Assembly of platforms for signal transduction in the new era: dimerization, helical filament assembly, and beyond

Chun

Park

2020

Exp Mol Med

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“…42-44 and Figure 2A), and a central catalytic domain that shares homology with the proteolytic active site of the caspase family of serine proteases (43). MALT1 also contains an N-terminal death domain (DD), and recent studies suggest that this domain may interact with BCL10 (44). Interestingly, co-IP mapping studies revealed that GRK2 binds to this MALT1 DD (amino acids 1-139) ( Figure 2A).…”

Section: Introductionmentioning

confidence: 97%

GRK2 suppresses lymphomagenesis by inhibiting the MALT1 proto-oncoprotein

Cheng¹,

Klei²,

Hubel³

et al. 2020

Journal of Clinical Investigation

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“…In effector T cells, the CBM complex forms the core of a filamentous assembly called the POLKADOTS signalosome, which serves as the cytoplasmic site of the terminal steps of the NF-κB-activation cascade (13,14,(18)(19)(20)(21). Contemporaneously with assembly into microns-long filaments, Bcl10 is also degraded (13,(22)(23)(24)(25)(26), and we have previously shown that proteolysis of Bcl10 occurs within the POLKADOTS signalosome via TCR-dependent selective autophagy (18).…”

Section: Introductionmentioning

confidence: 99%

“…Several key details of this polymerization process are known: recent cell-free cryo-electronmicroscopy studies revealed that Bcl10 polymerizes into filaments with a geometrically confined, helical arrangement with other POLKADOTS components (14,20,21). Although the core of the POLKADOTS filament is composed primarily of Bcl10, polymerization of Bcl10 is nucleated by short oligomers of Carma1and the Carma1-driven nucleation of Bcl10 can act as an amplifier of activation signals from the T cell receptor to NF-κB (14).…”

Section: Introductionmentioning

confidence: 99%

Signaling through polymerization and degradation: Analysis and simulations of T cell activation mediated by Bcl10

Campanello

Traver

Shroff

et al. 2020

Preprint

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The adaptive immune system serves as a potent and highly specific defense mechanism against pathogen infection. One component of this system, the effector T cell, facilitates pathogen clearance upon detection of specific antigens by the T cell receptor (TCR). A critical process in effector T cell activation is transmission of signals from the TCR to a key transcriptional regulator, NF-κB. The transmission of this signal involves a highly dynamic process in which helical filaments of Bcl10, a key protein constituent of the TCR signaling cascade, undergo competing processes of polymeric assembly and macroautophagydependent degradation. Through computational analysis of three-dimensional super-resolution microscopy data, we quantitatively characterized TCR-stimulated Bcl10 filament assembly and length dynamics, demonstrating that filaments become shorter over time. Additionally, we developed an imagebased bootstrap-like resampling method to quantitatively demonstrate preferred association between autophagosomes and Bcl10-filament ends and punctate-Bcl10 structures, implying that autophagosomedriven macroautophagy is directly responsible for Bcl10 filament shortening. We probe Bcl10 polymerization-depolymerization dynamics with a stochastic Monte-Carlo simulation of nucleation-limited filament assembly and degradation, and we show that high probabilities of filament nucleation in response to TCR engagement could provide the observed robust, homogeneous, and tunable response dynamic. Furthermore, the speed of autophagic degradation of filaments preferentially at filament ends provides effective regulatory control. Taken together, these data suggest that Bcl10 filament growth and degradation act as an excitable system that provides a digital response mechanism and the reliable timing critical for T cell activation and regulatory processes. Author SummaryThe immune system serves to protect organisms against pathogen-mediated disease. While a strong immune response is needed to eliminate pathogens in host organisms, immune responses that are too robust or too persistent can trigger autoimmune disorders, cancer, and a variety of additional serious human pathologies. Thus, a careful balance of activating and inhibitory mechanisms are necessary to prevent detrimental health outcomes of immune responses. For example, activated effector T cells marshal the immune response and direct killing of pathogen-infected cells; however, effector T cells that are chronically activated can damage and destroy healthy tissue. Here, we study an important internal activation pathway in effector T cells that involves the growth and counterbalancing degradation (via a process called macroautophagy) of filamentous cytoplasmic signaling structures. We utilize image analysis of 3-D super-resolution images and Monte Carlo simulations to study a key signal-transduction protein, Bcl10. We found that the speed of filament degradation has the greatest effect on the magnitude and duration of the response, implying that pharmaceutical interventions aime...

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Molecular architecture and regulation of BCL10-MALT1 filaments

Cited by 56 publications

References 63 publications

Assembly of platforms for signal transduction in the new era: dimerization, helical filament assembly, and beyond

Assembly of platforms for signal transduction in the new era: dimerization, helical filament assembly, and beyond

GRK2 suppresses lymphomagenesis by inhibiting the MALT1 proto-oncoprotein

Signaling through polymerization and degradation: Analysis and simulations of T cell activation mediated by Bcl10

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