title: The autophagy regulator Rubicon is a feedback inhibitor of CARD9-mediated host innate immunity.
abstract: Assembly of a scaffold consisting of CARD9, BCL10, and MALT1 (CBM complex) is critical for effective signaling by multiple pattern recognition receptors (PRRs) including Dectin and RIG-I. The RUN domain Beclin-1-interacting cysteine-rich-containing Rubicon protein associates constitutively with the Beclin-UVRAG-Vps34 complex under normal conditions to regulate autophagy. Rubicon also interacts with the phagocytic NADPH-oxidase complex upon TLR stimulation to induce potent antimicrobial responses. Here, we show Rubicon is a physiological feedback inhibitor of CBM-mediated PRR signaling, preventing unbalanced proinflammatory responses. Upon Dectin-1- or RIG-I-mediated activation, Rubicon dynamically exchanges binding partners from 14-3-3β to CARD9 in a stimulation-specific and phosphorylation-dependent manner, disassembling the CBM signaling complex and ultimately terminating PRR-induced cytokine production. Remarkably, Rubicon's actions in the autophagy complex, phagocytosis complex, and CBM complex are functionally and genetically separable. Rubicon thus differentially targets signaling complexes, depending on environmental stimuli, and may function to coordinate various immune responses against microbial infection.
authors.affiliation: Department of Molecular Microbiology and Immunology, University of Southern California, Keck School of Medicine, Los Angeles, CA 90033, USA.
authors.forename: Chul-Su
authors.initials: CS
authors.lastname: Yang
authors.forename: Mary
authors.initials: M
authors.lastname: Rodgers
authors.forename: Chan-Ki
authors.initials: CK
authors.lastname: Min
authors.forename: Jong-Soo
authors.initials: JS
authors.lastname: Lee
authors.forename: Lara
authors.initials: L
authors.lastname: Kingeter
authors.forename: June-Yong
authors.initials: JY
authors.lastname: Lee
authors.forename: Ambrose
authors.initials: A
authors.lastname: Jong
authors.forename: Igor
authors.initials: I
authors.lastname: Kramnik
authors.forename: Xin
authors.initials: X
authors.lastname: Lin
authors.forename: Jae U
authors.initials: JU
authors.lastname: Jung
mesh_terms: D048948:14-3-3 Proteins / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D000071183:Autophagy-Related Proteins; D000074018:B-Cell CLL-Lymphoma 10 Protein; D001667:Binding, Competitive; D053468:CARD Signaling Adaptor Proteins / Q000378:metabolism*; D002176:Candida albicans / Q000254:growth & development / Q000276:immunology / Q000502:physiology; D002177:Candidiasis / Q000276:immunology / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D025461:Feedback, Physiological; D054884:Host-Pathogen Interactions; D006801:Humans; D007113:Immunity, Innate; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism / Q000502:physiology*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D051379:Mice; D008822:Mice, Transgenic; D050296:Microbial Viability; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; D046912:Multiprotein Complexes / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism; D009976:Orthomyxoviridae Infections / Q000276:immunology / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D015398:Signal Transduction
chemical_list: D048948:14-3-3 Proteins; D048868:Adaptor Proteins, Signal Transducing; D000071183:Autophagy-Related Proteins; D000074018:B-Cell CLL-Lymphoma 10 Protein; C118591:BCL10 protein, human; D053468:CARD Signaling Adaptor Proteins; C505855:CARD9 protein, human; D016207:Cytokines; D047908:Intracellular Signaling Peptides and Proteins; D046912:Multiprotein Complexes; D009363:Neoplasm Proteins; C552537:RUBCN protein, human; C482982:YWHAB protein, human; D020169:Caspases; C400109:MALT1 protein, human; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein