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1.
Nat Immunol ; 19(1): 63-75, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29203862

RESUMO

Innate immune cells adjust to microbial and inflammatory stimuli through a process termed environmental plasticity, which links a given individual stimulus to a unique activated state. Here, we report that activation of human plasmacytoid predendritic cells (pDCs) with a single microbial or cytokine stimulus triggers cell diversification into three stable subpopulations (P1-P3). P1-pDCs (PD-L1+CD80-) displayed a plasmacytoid morphology and specialization for type I interferon production. P3-pDCs (PD-L1-CD80+) adopted a dendritic morphology and adaptive immune functions. P2-pDCs (PD-L1+CD80+) displayed both innate and adaptive functions. Each subpopulation expressed a specific coding- and long-noncoding-RNA signature and was stable after secondary stimulation. P1-pDCs were detected in samples from patients with lupus or psoriasis. pDC diversification was independent of cell divisions or preexisting heterogeneity within steady-state pDCs but was controlled by a TNF autocrine and/or paracrine communication loop. Our findings reveal a novel mechanism for diversity and division of labor in innate immune cells.


Assuntos
Citocinas/imunologia , Células Dendríticas/imunologia , Expressão Gênica/imunologia , Imunidade Inata/imunologia , Imunidade Adaptativa/imunologia , Antígeno B7-1/imunologia , Antígeno B7-1/metabolismo , Antígeno B7-H1/imunologia , Antígeno B7-H1/metabolismo , Células Cultivadas , Citocinas/genética , Citocinas/metabolismo , Células Dendríticas/metabolismo , Células Dendríticas/ultraestrutura , Perfilação da Expressão Gênica/métodos , Humanos , Interferon Tipo I/genética , Interferon Tipo I/imunologia , Interferon Tipo I/metabolismo , Lúpus Eritematoso Sistêmico/imunologia , Microscopia Eletrônica de Transmissão , Orthomyxoviridae/imunologia , Psoríase/imunologia
2.
J Biol Chem ; 288(23): 16460-16475, 2013 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-23609449

RESUMO

Here we report for the first time the three-dimensional structure of a mannose 6-phosphate receptor homology (MRH) domain present in a protein with enzymatic activity, glucosidase II (GII). GII is involved in glycoprotein folding in the endoplasmic reticulum. GII removes the two innermost glucose residues from the Glc3Man9GlcNAc2 transferred to nascent proteins and the glucose added by UDP-Glc:glycoprotein glucosyltransferase. GII is composed of a catalytic GIIα subunit and a regulatory GIIß subunit. GIIß participates in the endoplasmic reticulum localization of GIIα and mediates in vivo enhancement of N-glycan trimming by GII through its C-terminal MRH domain. We determined the structure of a functional GIIß MRH domain by NMR spectroscopy. It adopts a ß-barrel fold similar to that of other MRH domains, but its binding pocket is the most shallow known to date as it accommodates a single mannose residue. In addition, we identified a conserved residue outside the binding pocket (Trp-409) present in GIIß but not in other MRHs that influences GII glucose trimming activity.


Assuntos
Retículo Endoplasmático , Glicoproteínas , Dobramento de Proteína , Proteínas de Schizosaccharomyces pombe , Schizosaccharomyces/enzimologia , alfa-Glucosidases , Cristalografia por Raios X , Retículo Endoplasmático/química , Retículo Endoplasmático/genética , Retículo Endoplasmático/metabolismo , Glicoproteínas/química , Glicoproteínas/genética , Glicoproteínas/metabolismo , Manose/química , Manose/genética , Manose/metabolismo , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína , Schizosaccharomyces/genética , Proteínas de Schizosaccharomyces pombe/química , Proteínas de Schizosaccharomyces pombe/genética , Proteínas de Schizosaccharomyces pombe/metabolismo , alfa-Glucosidases/química , alfa-Glucosidases/genética , alfa-Glucosidases/metabolismo
3.
Mol Biol Cell ; 22(11): 1810-23, 2011 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-21471007

RESUMO

Glucosidase II (GII) sequentially removes the two innermost glucose residues from the glycan (Glc(3)Man(9)GlcNAc(2)) transferred to proteins. GII also participates in cycles involving the lectin/chaperones calnexin (CNX) and calreticulin (CRT) as it removes the single glucose unit added to folding intermediates and misfolded glycoproteins by the UDP-Glc:glycoprotein glucosyltransferase (UGGT). GII is a heterodimer in which the α subunit (GIIα) bears the active site, and the ß subunit (GIIß) modulates GIIα activity through its C-terminal mannose 6-phosphate receptor homologous (MRH) domain. Here we report that, as already described in cell-free assays, in live Schizosaccharomyces pombe cells a decrease in the number of mannoses in the glycan results in decreased GII activity. Contrary to previously reported cell-free experiments, however, no such effect was observed in vivo for UGGT. We propose that endoplasmic reticulum α-mannosidase-mediated N-glycan demannosylation of misfolded/slow-folding glycoproteins may favor their interaction with the lectin/chaperone CNX present in S. pombe by prolonging the half-lives of the monoglucosylated glycans (S. pombe lacks CRT). Moreover, we show that even N-glycans bearing five mannoses may interact in vivo with the GIIß MRH domain and that the N-terminal GIIß G2B domain is involved in the GIIα-GIIß interaction. Finally, we report that protists that transfer glycans with low mannose content to proteins have nevertheless conserved the possibility of displaying relatively long-lived monoglucosylated glycans by expressing GIIß MRH domains with a higher specificity for glycans with high mannose content.


Assuntos
Glicoproteínas/metabolismo , Manose/metabolismo , Schizosaccharomyces/enzimologia , alfa-Glucosidases/metabolismo , Sequência de Carboidratos , Retículo Endoplasmático/metabolismo , Técnicas de Inativação de Genes , Glucosiltransferases/genética , Glucosiltransferases/metabolismo , Meia-Vida , Hexosiltransferases/metabolismo , Dados de Sequência Molecular , Polissacarídeos/química , Polissacarídeos/metabolismo , Dobramento de Proteína , Domínios e Motivos de Interação entre Proteínas , Estabilidade Proteica , Estrutura Terciária de Proteína , Schizosaccharomyces/genética , alfa-Glucosidases/genética , alfa-Manosidase
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