Receptor Heterodimerization and Co-Receptor Engagement in TLR2 Activation Induced by MIC1 and MIC4 from Toxoplasma gondii

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Mendonca-Natividade, Flavia Costa ^[1] ; Lopes, Carla Duque ^[1] ; Ricci-Azevedo, Rafael ^[1] ; Sardinha-Silva, Aline ^[1] ; Pinzan, Camila Figueiredo ^[1] ; Paiva Alegre-Maller, Ana Claudia ^[1] ; Nohara, Lilian L. ^[2] ; Carneiro, Alan B. ^{[2, 3]} ; Panunto-Castelo, Ademilson ^[4] ; Almeida, Igor C. ^[2] ; Roque-Barreira, Maria Cristina ^[1]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo FMRP USP, Ribeirao Preto Med Sch, Dept Cell & Mol Biol & Pathogen Bioagents, Lab Immunochem & Glycobiol, BR-14049900 Ribeirao Preto, SP - Brazil

^[2] Univ Texas El Paso, Dept Biol Sci, BBRC, El Paso, TX 79968 - USA

^[3] Fed Univ Rio de Janeiro UFRJ, Inst Med Biochem, Program Mol Biol & Biotechnol, BR-21941599 Rio De Janeiro, RJ - Brazil

^[4] Univ Sao Paulo USP FFCLRP USP, Dept Biol, Fac Philosophy Sci & Letters Ribeirao Preto, BR-14040900 Ribeirao Preto, SP - Brazil

• Tipo de documento: Artigo Científico
• Fonte: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES; v. 20, n. 20 OCT 2 2019.
• Citações Web of Science: 0

Resumo

The microneme organelles of Toxoplasma gondii tachyzoites release protein complexes (MICs), including one composed of the transmembrane protein MIC6 plus MIC1 and MIC4. In this complex, carbohydrate recognition domains of MIC1 and MIC4 are exposed and interact with terminal sialic acid and galactose residues, respectively, of host cell glycans. Recently, we demonstrated that MIC1 and MIC4 binding to the N-glycans of Toll-like receptor (TLR) 2 and TLR4 on phagocytes triggers cell activation and pro-inflammatory cytokine production. Herein, we investigated the requirement for TLR2 heterodimerization and co-receptors in MIC-induced responses, as well as the signaling molecules involved. We used MICs to stimulate macrophages and HEK293T cells transfected with TLR2 and TLR1 or TLR6, both with or without the co-receptors CD14 and CD36. Then, the cell responses were analyzed, including nuclear factor-kappa B (NF-kappa B) activation and cytokine production, which showed that (1) only TLR2, among the studied factors, is crucial for MIC-induced cell activation; (2) TLR2 heterodimerization augments, but is not critical for, activation; (3) CD14 and CD36 enhance the response to MIC stimulus; and (4) MICs activate cells through a transforming growth factor beta-activated kinase 1 (TAK1)-, mammalian p38 mitogen-activated protein kinase (p38)-, and NF-kappa B-dependent pathway. Remarkably, among the studied factors, the interaction of MIC1 and MIC4 with TLR2 N-glycans is sufficient to induce cell activation, which promotes host protection against T. gondii infection. (AU)

• Processo FAPESP: 13/04088-0 - Lectinas de patógenos
• Beneficiário: Maria Cristina Roque Antunes Barreira
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 17/02998-0 - Efeitos de Toxoplasma gondii e Paracoccidioides brasiliensis, exercidos através de suas respectivas lectinas sobre vias intracelulares ativadas pelo reconhecimento de glicanos N-ligados a receptores do tipo Toll em neutrófilos
• Beneficiário: Rafael Ricci de Azevedo
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 14/13324-1 - Interação de proteínas de micronema de Toxoplasma gondii com glicanas N-ligadas a TLR4: reflexos sobre a imunidade inata
• Beneficiário: Flávia Costa Mendonça Natividade
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 08/52130-7 - Proteinas de micronemas de t.gondii: novos papeis atribuiveis a sua interacao com receptores do tipo toll.
• Beneficiário: Carla Duque Lopes
• Modalidade de apoio: Bolsas no Brasil - Doutorado