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1.
Mol Cell Biol ; 37(11)2017 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-28265003

RESUMO

Interleukin-6 (IL-6) is a multifunctional cytokine with important functions in various physiologic processes. Mice lacking IL-6 exhibit multiple phenotypic abnormalities, such as an inadequate immune and acute-phase response, and elevated levels of circulating IL-6 have been found to accompany several pathological conditions. IL-6 binds the nonsignaling IL-6 receptor (IL-6R), which is expressed as a transmembrane, as well as a secreted circulating protein, before it engages homodimeric gp130 for signaling. Complex formation between IL-6 and the membrane-bound IL-6 receptor gives rise to classic cis signaling, whereas complex formation between IL-6 and the soluble IL-6R results in trans signaling. Here, we report that the endocytic receptor SorLA targets IL-6 and IL-6R. We present evidence that SorLA mediates efficient cellular uptake of both IL-6 and the circulating IL-6R in astrocytes. We further show that SorLA interacts with the membrane-bound IL-6R at the cell surface and thereby downregulates IL-6 cis signaling. Finally, we find that the SorLA ectodomain, released from the cell membrane upon enzymatic cleavage of full-length SorLA, may act as an IL-6 carrier protein that stabilizes IL-6 and its capacity for trans signaling.


Assuntos
Interleucina-6/metabolismo , Proteínas Relacionadas a Receptor de LDL/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Receptores de LDL/metabolismo , Transdução de Sinais , Animais , Astrócitos/metabolismo , Membrana Celular/metabolismo , Regulação para Baixo , Endocitose , Células HEK293 , Meia-Vida , Humanos , Camundongos Knockout , Peptídeos/metabolismo , Ligação Proteica , Domínios Proteicos , Estabilidade Proteica , Receptores de Interleucina-6/química , Receptores de Interleucina-6/metabolismo , Solubilidade , Transfecção
2.
Mol Cell Biol ; 36(8): 1272-86, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26858303

RESUMO

Cardiotrophin-like cytokine:cytokine-like factor-1 (CLC:CLF-1) is a heterodimeric neurotropic cytokine that plays a crucial role during neuronal development. Mice lacking CLC:CLF-1 die soon after birth due to a suckling defect and show reduced numbers of motor neurons. Humans carrying mutations in CLC:CLF-1 develop similar disorders, known as Sohar-Crisponi or cold-induced sweating syndrome, and have a high risk of early death. It is well known that CLC binds the ciliary neurotrophic factor receptor α (CNTFRα) and is a prerequisite for signaling through the gp130/leukemia inhibitory factor receptor ß (LIFRß) heterodimer, whereas CLF-1 serves to promote the cellular release of CLC. However, the precise role of CLF-1 is unclear. Here, we report that CLF-1, based on its binding site for CLC and on two additional and independent sites for CNTFRα and sorLA, is a key player in CLC and CNTFRα signaling and turnover. The site for CNTFRα enables CLF-1 to promote CLC:CNTFRα complex formation and signaling. The second site establishes a link between the endocytic receptor sorLA and the tripartite CLC:CLF-1:CNTFRα complex and allows sorLA to downregulate the CNTFRα pool in stimulated cells. Finally, sorLA may bind and concentrate the tripartite soluble CLC:CLF-1:CNTFRα complex on cell membranes and thus facilitate its signaling through gp130/LIFRß.


Assuntos
Subunidade alfa do Receptor do Fator Neutrófico Ciliar/metabolismo , Citocinas/metabolismo , Proteínas Relacionadas a Receptor de LDL/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Receptores de Citocinas/metabolismo , Transdução de Sinais , Células HEK293 , Humanos , Ligação Proteica
3.
J Cell Sci ; 127(Pt 16): 3477-87, 2014 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-24928897

RESUMO

Here, we describe altered sorting of sortilin in adipocytes deficient for the σ1B-containing AP-1 complex, leading to the inhibition of adipogenesis. The AP-1 complex mediates protein sorting between the trans-Golgi network and endosomes. Vertebrates express three AP1 σ1 subunit isoforms - σ1A, σ1B and σ1C (also known as AP1S1, AP1S2 and AP1S3, respectively). σ1B-deficient mice display impaired recycling of synaptic vesicles and lipodystrophy. Here, we show that sortilin is overexpressed in adipose tissue from σ1B(-/-) mice, and that its overexpression in wild-type cells is sufficient to suppress adipogenesis. σ1B-specific binding of sortilin requires the sortilin DxxD-x12-DSxxxL motif. σ1B deficiency does not lead to a block of sortilin transport out of a specific organelle, but the fraction that reaches lysosomes is reduced. Sortilin binds to the receptor DLK1, an inhibitor of adipocyte differentiation, and the overexpression of sortilin prevents DLK1 downregulation, leading to enhanced inhibition of adipogenesis. DLK1 and sortilin expression are not increased in the brain tissue of σ1B(-/-) mice, although this is the tissue with the highest expression of σ1B and sortilin. Thus, adipose-tissue-specific and σ1B-dependent routes for the transport of sortilin exist and are involved in the regulation of adipogenesis and adipose-tissue mass.


Assuntos
Complexo 1 de Proteínas Adaptadoras/metabolismo , Subunidades sigma do Complexo de Proteínas Adaptadoras/metabolismo , Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Adipócitos/metabolismo , Adipogenia , Tecido Adiposo/metabolismo , Complexo 1 de Proteínas Adaptadoras/genética , Subunidades sigma do Complexo de Proteínas Adaptadoras/genética , Proteínas Adaptadoras de Transporte Vesicular/genética , Adipócitos/citologia , Tecido Adiposo/citologia , Animais , Feminino , Masculino , Camundongos , Camundongos Knockout , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Transporte Proteico
4.
Biochem J ; 457(2): 277-88, 2014 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-24128306

RESUMO

Sortilin and sorCS1 [sortilin-related Vps10p (vacuolar protein sorting/targeting protein 10) domain-containing receptor 1], both members of the Vps10p-D (Vps10p-domain) receptor family, are synthesized as precursor proteins and are converted into their mature form by enzymatic cleavage of a short N-terminal propeptide. SorCS1 does not bind its propeptide, but sortilin is able to bind not just its own propeptide, but also that of sorCS1. In the present study we show that the propeptide region of sorCS1 contains two separate sites for binding to sortilin and that only one of these sites is removed from human (as opposed to mouse) sorCS1 during processing. This leaves mature human sorCS1 with a sortilin-binding N-terminus, which allows formation of a complex between the two receptors in solution and on cell membranes. Furthermore, we find that the interaction with sorCS1 has a pronounced effect on sortilin's ability to mediate the cellular uptake of alternative ligands, and to hamper its facilitation of CNTF (ciliary neutrophic factor) signalling and the induction of phosphorylated STAT3 (signal transducer and activator of transcription 3). Thus the present study reveals a novel regulatory mechanism and suggest an entirely new role for sorCS1 as a modulator of sortilin function.


Assuntos
Proteínas Adaptadoras de Transporte Vesicular/antagonistas & inibidores , Proteínas Adaptadoras de Transporte Vesicular/genética , Receptores de Superfície Celular/metabolismo , Animais , Células CHO , Membrana Celular/genética , Cricetinae , Cricetulus , Células HEK293 , Humanos , Ligação Proteica/genética , Precursores de Proteínas/genética , Precursores de Proteínas/metabolismo , Processamento de Proteína Pós-Traducional , Receptores de Superfície Celular/antagonistas & inibidores , Receptores de Superfície Celular/genética
5.
Mol Cell Biol ; 30(17): 4175-87, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20584990

RESUMO

Sortilin is a member of the Vps10p domain family of neuropeptide and neurotrophin binding neuronal receptors. The family members interact with and partly share a variety of ligands and partake in intracellular sorting and protein transport as well as in transmembrane signal transduction. Thus, sortilin mediates the transport of both neurotensin and nerve growth factor and interacts with their respective receptors to facilitate ligand-induced signaling. Here we report that ciliary neurotrophic factor (CNTF), and related ligands targeting the established CNTF receptor alpha, binds to sortilin with high affinity. We find that sortilin may have at least two functions: one is to provide rapid endocytosis and the removal of CNTF, something which is not provided by CNTF receptor alpha, and the other is to facilitate CNTF signaling through the gp130/leukemia inhibitory factor (LIF) receptor beta heterodimeric complex. Interestingly, the latter function is independent of both the CNTF receptor alpha and ligand binding to sortilin but appears to implicate a direct interaction with LIF receptor beta. Thus, sortilin facilitates the signaling of all helical type 1 cytokines, which engage the gp130/LIF receptor beta complex.


Assuntos
Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Fator Neurotrófico Ciliar/metabolismo , Receptor gp130 de Citocina/metabolismo , Animais , Linhagem Celular , Proliferação de Células , Citocinas/metabolismo , Humanos , Interleucina-6/metabolismo , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Fosforilação , Ligação Proteica , Receptores de Citocinas/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais
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