RESUMO
The Par polarity complex, consisting of Par3, Par6 and atypical protein kinase C (aPKC), plays a crucial role in the establishment and maintenance of cell polarity. Although activation of aPKC is critical for polarity, how this is achieved is unclear. The developing zebrafish epidermis, along with its apical actin-based projections, called microridges, offers a genetically tractable system for unraveling the mechanisms of the cell polarity control. The zebrafish aPKC regulates elongation of microridges by controlling levels of apical Lgl, which acts as a pro-elongation factor. Here, we show that the nucleoporin Nup358 (also known as RanBP2) - a component of the nuclear pore complex and a part of cytoplasmic annulate lamellae (AL) - SUMOylates zebrafish aPKC. Nup358-mediated SUMOylation controls aPKC activity to regulate Lgl-dependent microridge elongation. Our data further suggest that cytoplasmic AL structures are the possible site for Nup358-mediated aPKC SUMOylation. We have unraveled a hitherto unappreciated contribution of Nup358-mediated aPKC SUMOylation in cell polarity regulation.This article has an associated First Person interview with the first author of the paper.
Assuntos
Polaridade Celular/fisiologia , Células Epidérmicas/metabolismo , Chaperonas Moleculares/metabolismo , Complexo de Proteínas Formadoras de Poros Nucleares/metabolismo , Peixe-Zebra/metabolismo , Actinas/metabolismo , Animais , Epiderme/metabolismo , Células Epiteliais/metabolismo , Chaperonas Moleculares/genética , Complexo de Proteínas Formadoras de Poros Nucleares/genética , Peixe-Zebra/embriologia , Peixe-Zebra/genéticaRESUMO
Epithelial cells exhibit apical membrane protrusions, which confer specific functions to epithelial tissues. Microridges are short actin protrusions that are laterally long and form a maze-like pattern in the apical domain. They are widely found on vertebrate squamous epithelia including epidermis and have functions in mucous retention, membrane storage and abrasion resistance. It is largely unknown how the formation of these laterally long actin projections is regulated. Here, we show that antagonistic interactions between aPKC and Lgl-regulators of apical and basolateral domain identity, respectively,-control the length of microridges in the zebrafish periderm, the outermost layer of the epidermis. aPKC regulates the levels of Lgl and the active form of non-muscle myosinII at the apical cortex to prevent actin polymerization-dependent precocious fusion and elongation of microridges. Our data unravels the functional significance of exclusion of Lgl from the apical domain in epithelial cells.
Assuntos
Epiderme/metabolismo , Células Epiteliais/metabolismo , Glicoproteínas/metabolismo , Proteína Quinase C/metabolismo , Proteínas de Peixe-Zebra/metabolismo , Peixe-Zebra/genética , Citoesqueleto de Actina/genética , Citoesqueleto de Actina/metabolismo , Citoesqueleto de Actina/ultraestrutura , Actinas/genética , Actinas/metabolismo , Animais , Animais Geneticamente Modificados , Polaridade Celular , Embrião não Mamífero , Desenvolvimento Embrionário/genética , Células Epidérmicas , Epiderme/crescimento & desenvolvimento , Células Epiteliais/ultraestrutura , Regulação da Expressão Gênica no Desenvolvimento , Glicoproteínas/antagonistas & inibidores , Glicoproteínas/genética , Morfolinos/genética , Morfolinos/metabolismo , Miosina Tipo II/genética , Miosina Tipo II/metabolismo , Proteína Quinase C/genética , Peixe-Zebra/crescimento & desenvolvimento , Peixe-Zebra/metabolismo , Proteínas de Peixe-Zebra/antagonistas & inibidores , Proteínas de Peixe-Zebra/genéticaRESUMO
FCGR2A and CCL2 gene variants are important in dengue pathogenesis and were investigated in 122 dengue patients (DENs) [89 dengue fever (DF) and 33 dengue hemorrhagic fever (DHF)] and 107 healthy controls (HCs) to find out their association with severity of dengue. Genotype frequencies of FCGR2A p.R131H and CCL2 c.-2518 A > G polymorphisms were not different between DF, DHF and HC. Significantly higher frequency of R/R genotype of FCGR2A p.R131H was observed in DEN cases with thrombocytopenia (TP) while the G/G genotype of CCL2 c.-2518 A > G was observed only in DEN cases with TP (p < 0.005). These results suggest that FCGR2A and CCL2 gene variants were associated with the risk of TP in dengue infections.
Assuntos
Quimiocina CCL2/genética , Vírus da Dengue , Dengue/complicações , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Receptores de IgG/genética , Trombocitopenia/etiologia , Adulto , Alelos , Estudos de Casos e Controles , Dengue/genética , Feminino , Frequência do Gene , Estudos de Associação Genética , Genótipo , Humanos , Masculino , Razão de Chances , Dengue Grave/complicações , Dengue Grave/genética , Adulto JovemRESUMO
Dendritic cell specific intercellular adhesion molecule 3 grabbing non-integrin, coded by the CD209 gene, acts as an entry receptor for dengue virus. Polymorphisms in the promoter region of CD209 gene (rs735239, rs4804803, rs2287886) were investigated in 112 hospitalized cases of dengue (DEN) and 104 healthy controls to find out whether they are associated with dengue in a Western Indian population. Results revealed a significantly higher frequency of 'G' allele and 'G/G' genotype of rs2287886 and A-A-G haplotype of CD209 gene in DEN compared to healthy controls [For 'G/G' genotype, P=0.0072, Odds ratio (OR) 2.43; For A-A-G haplotype, P=0.0033, OR 2]. The frequency of A/A genotype of rs735239 was higher in DEN cases with thrombocytopenia compared to cases without thrombocytopenia (P=0.026). The results suggest that rs2287886 G/G genotype of CD209 gene is associated with development of dengue requiring hospitalization while A/A genotype of rs735239 is associated with thrombocytopenia in dengue cases.
