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1.
PLoS Biol ; 19(7): e3001361, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34297722

RESUMO

The lysosome is an essential organelle to recycle cellular materials and maintain nutrient homeostasis, but the mechanism to down-regulate its membrane proteins is poorly understood. In this study, we performed a cycloheximide (CHX) chase assay to measure the half-lives of approximately 30 human lysosomal membrane proteins (LMPs) and identified RNF152 and LAPTM4A as short-lived membrane proteins. The degradation of both proteins is ubiquitin dependent. RNF152 is a transmembrane E3 ligase that ubiquitinates itself, whereas LAPTM4A uses its carboxyl-terminal PY motifs to recruit NEDD4-1 for ubiquitination. After ubiquitination, they are internalized into the lysosome lumen by the endosomal sorting complexes required for transport (ESCRT) machinery for degradation. Strikingly, when ectopically expressed in budding yeast, human RNF152 is still degraded by the vacuole (yeast lysosome) in an ESCRT-dependent manner. Thus, our study uncovered a conserved mechanism to down-regulate lysosome membrane proteins.


Assuntos
Complexos Endossomais de Distribuição Requeridos para Transporte/metabolismo , Membranas Intracelulares/metabolismo , Lisossomos/metabolismo , Proteínas de Membrana/metabolismo , Humanos , Proteólise , Ubiquitina-Proteína Ligases/metabolismo
2.
J Cell Biol ; 220(1)2021 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-33351099

RESUMO

While it is well-known that E3 ubiquitin ligases can selectively ubiquitinate membrane proteins in response to specific environmental cues, the underlying mechanisms for the selectivity are poorly understood. In particular, the role of transmembrane regions, if any, in target recognition remains an open question. Here, we describe how Ssh4, a yeast E3 ligase adaptor, recognizes the PQ-loop lysine transporter Ypq1 only after lysine starvation. We show evidence of an interaction between two transmembrane helices of Ypq1 (TM5 and TM7) and the single transmembrane helix of Ssh4. This interaction is regulated by the conserved PQ motif. Strikingly, recent structural studies of the PQ-loop family have suggested that TM5 and TM7 undergo major conformational changes during substrate transport, implying that transport-associated conformational changes may determine the selectivity. These findings thus provide critical information concerning the regulatory mechanism through which transmembrane domains can be specifically recognized in response to changing environmental conditions.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Membrana Celular/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Sequência de Aminoácidos , Sítios de Ligação , Genes Supressores , Proteínas de Fluorescência Verde/metabolismo , Modelos Biológicos , Mutagênese/genética , Mutação/genética , Estrutura Secundária de Proteína , Proteólise , Reprodutibilidade dos Testes , Proteínas de Saccharomyces cerevisiae/química , Homologia Estrutural de Proteína
3.
J Cell Biol ; 219(3)2020 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-32045480

RESUMO

Cellular adaptation in response to nutrient limitation requires the induction of autophagy and lysosome biogenesis for the efficient recycling of macromolecules. Here, we discovered that starvation and TORC1 inactivation not only lead to the up-regulation of autophagy and vacuole proteins involved in recycling but also result in the down-regulation of many vacuole membrane proteins to supply amino acids as part of a vacuole remodeling process. Down-regulation of vacuole membrane proteins is initiated by ubiquitination, which is accomplished by the coordination of multiple E3 ubiquitin ligases, including Rsp5, the Dsc complex, and a newly characterized E3 ligase, Pib1. The Dsc complex is negatively regulated by TORC1 through the Rim15-Ume6 signaling cascade. After ubiquitination, vacuole membrane proteins are sorted into the lumen for degradation by ESCRT-dependent microautophagy. Thus, our study uncovered a complex relationship between TORC1 inactivation and vacuole biogenesis.


Assuntos
Complexos Endossomais de Distribuição Requeridos para Transporte/metabolismo , Membranas Intracelulares/enzimologia , Microautofagia , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/enzimologia , Fatores de Transcrição/metabolismo , Ubiquitina/metabolismo , Vacúolos/enzimologia , Complexos Endossomais de Distribuição Requeridos para Transporte/genética , Proteínas Quinases/genética , Proteínas Quinases/metabolismo , Transporte Proteico , Proteólise , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/genética , Transdução de Sinais , Fatores de Tempo , Fatores de Transcrição/genética , Complexos Ubiquitina-Proteína Ligase/genética , Complexos Ubiquitina-Proteína Ligase/metabolismo , Ubiquitinação , Vacúolos/genética
4.
Chin Med J (Engl) ; 128(4): 528-32, 2015 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-25673458

RESUMO

BACKGROUND: Increasing evidence supports an association between periodontitis and systemic diseases. Leptin is involved both in the energy metabolism and inflammatory processes and is suggested to be a link between periodontal infection and systemic health. The present study aimed to evaluate the peripheral leptin concentration in patients with aggressive periodontitis (AgP) and to explore the relationship between leptin and systemic inflammation. METHODS: Ninety patients with AgP visiting the Clinic of the Periodontology Department, Peking University School and Hospital of Stomatology between July 2001 and May 2006, and 44 healthy controls (staff and student volunteers in the same institute) were recruited. Plasma levels of leptin and inflammatory cytokines including interleukin (IL)-1ß, IL-6, tumor necrosis factor-α (TNF-α) and C-reactive protein (CRP) were measured by enzyme-linked immunosorbent assay. Correlation and multiple linear regression analysis were performed to analyze the association between plasma leptin level and other variables. RESULTS: Plasma leptin level of AgP group was significantly higher than that of the control group (19.7 ± 4.4 ng/ml vs. 7.5 ± 1.3 ng/ml, P < 0.01). After controlling for age, gender, and body mass index, positive correlation was observed between plasma leptin concentration and log-transformed levels of pro-inflammatory cytokines (IL-1ß, IL-6, TNF-α and CRP), and the partial correlation coefficients ranged from 0.199 to 0.376 (P < 0.05). Log-transformed IL-1ß and IL-6 levels entered the final regression model (standardized ß were 0.422 and 0.461 respectively, P < 0.01). CONCLUSIONS: Elevated plasma leptin concentration may be associated with increased systemic levels of inflammatory markers in AgP patients.


Assuntos
Periodontite Agressiva/sangue , Periodontite Agressiva/imunologia , Leptina/sangue , Adolescente , Adulto , Proteína C-Reativa/metabolismo , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Interleucina-6/sangue , Masculino , Pessoa de Meia-Idade , Fator de Necrose Tumoral alfa/sangue , Adulto Jovem
5.
Zhonghua Kou Qiang Yi Xue Za Zhi ; 48(1): 3-6, 2013 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-23534512

RESUMO

OBJECTIVE: To detect the plasma leptin levels in patients with aggressive periodontitis (AgP) and to analyze the relationship between circulating leptin level and periodontal condition. METHODS: A total of 97 patients with AgP and 44 healthy controls were recruited. Detailed clinical examinations were conducted and clinical parameters such as bleeding index (BI), probing depth (PD), attachment loss (AL) were recorded. Plasma leptin level was measured by enzyme-linked immunosorbent assay. RESULTS: The plasma leptin level in AgP group was significantly higher than that of control subjects [(20.0 ± 4.3) µg/L vs. (7.5 ± 1.3) µg/L, P < 0.01)]. The plasma leptin level was positively related to BI, PD and AL, and the r values were 0.647, 0.596 and 0.632 respectively (P < 0.01). CONCLUSIONS: Plasma leptin concentration in AgP patients was significantly elevated compared with healthy controls. Circulating leptin level was positively related to periodontal parameters including BI, PD and AL.


Assuntos
Periodontite Agressiva/sangue , Leptina/sangue , Adolescente , Adulto , Periodontite Agressiva/diagnóstico , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Perda da Inserção Periodontal/sangue , Perda da Inserção Periodontal/diagnóstico , Índice Periodontal , Plasma/metabolismo , Adulto Jovem
6.
Acta Crystallogr Sect E Struct Rep Online ; 65(Pt 10): o2326, 2009 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-21577797

RESUMO

The title compound, C(14)H(10)N(2)O(4), shows crystallographic inversion symmetry and has one half-mol-ecule in the asymmetric unit. In the crystal, mol-ecules are linked into chains running along the cell diagonal by O-H⋯O hydrogen-bonding inter-actions.

7.
Acta Crystallogr Sect E Struct Rep Online ; 65(Pt 11): o2862, 2009 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-21578449

RESUMO

The pyran ring of the title compound, C(13)H(18)N(2)O(3), is almost planar (r.m.s. deviation = 0.059 Å). The crystal packing is stabilized by N-H⋯O and N-H⋯N hydrogen bonds.

8.
Acta Crystallogr Sect E Struct Rep Online ; 65(Pt 8): m978, 2009 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-21583421

RESUMO

In the title compound, [Ni(C(12)H(8)N(2))(H(2)O)(4)](C(12)H(10)O(8)), the Ni(II) ion is six-coordinated by two N atoms from one phenanthroline ligand and by the O atoms of four water mol-ecules in a distorted octa-hedral geometry. In the crystal, inter-molecular O-H⋯O hydrogen bonds form an extensive three-dimensional network, which consolidates the crystal packing.

9.
Acta Crystallogr Sect E Struct Rep Online ; 64(Pt 12): m1590, 2008 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-21581190

RESUMO

In the title compound, {[Cu(C(12)H(10)O(8))(C(12)H(8)N(2))]·H(2)O}(n), the Cu(II) ion is five-coordinated by two N atoms from one phenanthroline ligand and three O atoms from three different H(2)L(2-) anions (H(4)L is bicyclo-[2.2.2]oct-7-ene-2,3,5,6-tetra-carboxylic acid) in a distorted square-pyramidal geometry. Each H(2)L(2-) ion bridges three Cu(II) atoms to form a zigzag sheet parallel to the ab plane. The crystal structure is consolidated by O-H⋯O hydrogen bonds.

10.
Acta Crystallogr C ; 63(Pt 4): m159-60, 2007 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-17413220

RESUMO

In the title compound, poly[mu(5)-pyrazine-2,3-dicarboxylato-cadmium(II)], [Cd(C(6)H(2)N(2)O(4))](n) or [Cd(pdc)](n), where pdc is the pyrazine-2,3-dicarboxylate anion, the Cd(II) atom is six-coordinated by five carboxylate O atoms and one N atom from five different pdc ligands in a distorted octahedral CdO(5)N coordination geometry. Two Cd(II) atoms are bridged by carboxylate groups of the pdc ligands to create a dimeric unit. The dimeric units are further connected by the pdc ligands to generate an interesting two-dimensional structure.

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