RESUMO
Thioredoxin-interacting protein (TXNIP) has emerged as a key player in cancer and diabetes since it targets thioredoxin (TRX)-mediated redox regulation and glucose transporter (GLUT)-mediated metabolism. TXNIP consists of two arrestin (ARR, N-ARR and C-ARR) domains at its amino-terminus and two PPxY (PY) motifs and a di-leucine (LL) motif for endocytosis at its carboxyl-terminus. Here, we report that TXNIP shuffles between TRX and GLUTs to regulate homeostasis of intracellular oxidative stress and glucose metabolism. While TXNIP functions as a gatekeeper of TRX by default, it robustly interacted with class I GLUTs through its C-ARR domain upon increase of intracellular reactive oxygen species. This interaction prompted the surface expression downregulation and lysosomal degradation of GLUTs by its carboxyl-terminal LL endocytic signaling motif to attenuate glucose uptake. Consequently, TXNIP expression significantly limited glucose uptake, leading to the suppression of glycolysis, hexosamine biosynthesis, and the pentose phosphate pathway. Our findings establish a fundamental link between ROS and glucose metabolism through TXNIP and provide a promising target for the drug development against GLUT-related metabolic disorders.
Assuntos
Proteínas de Transporte , Diabetes Mellitus , Estresse Oxidativo , Tiorredoxinas , Humanos , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Glucose/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Tiorredoxinas/genética , Tiorredoxinas/metabolismo , Animais , CamundongosRESUMO
Hosts respond to viral infection by expressing interferon-stimulated genes, of which IFITs are potent inhibitors of viral RNA translation. Johnson et al. (2018) solved the structure of the IFIT1-IFIT3 complex bound cap 0 RNA and explored their concerted antiviral activity.
Assuntos
Proteínas de Transporte/genética , RNA Viral , Proteínas Adaptadoras de Transdução de Sinal , Síndromes Periódicas Associadas à Criopirina , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Biossíntese de Proteínas , Capuzes de RNA , Proteínas de Ligação a RNARESUMO
Blood CD14+ monocytes are frontline immunomodulators categorized into classical, intermediate or non-classical subsets, and subsequently differentiated into M1 pro- or M2 anti-inflammatory macrophages on stimulation. Although the Zika virus (ZIKV) rapidly establishes viraemia, the target cells and immune responses, particularly during pregnancy, remain elusive. Furthermore, it is unknown whether African- and Asian-lineage ZIKV have different phenotypic impacts on host immune responses. Using human blood infection, we identified CD14+ monocytes as the primary target for African- or Asian-lineage ZIKV infection. When immunoprofiles of human blood infected with ZIKV were compared, a classical/intermediate monocyte-mediated M1-skewed inflammation by the African-lineage ZIKV infection was observed, in contrast to a non-classical monocyte-mediated M2-skewed immunosuppression by the Asian-lineage ZIKV infection. Importantly, infection of the blood of pregnant women revealed an enhanced susceptibility to ZIKV infection. Specifically, Asian-lineage ZIKV infection of pregnant women's blood led to an exacerbated M2-skewed immunosuppression of non-classical monocytes in conjunction with a global suppression of type I interferon-signalling pathway and an aberrant expression of host genes associated with pregnancy complications. Also, 30 ZIKV+ sera from symptomatic pregnant patients showed elevated levels of M2-skewed immunosuppressive cytokines and pregnancy-complication-associated fibronectin-1. This study demonstrates the differential immunomodulatory responses of blood monocytes, particularly during pregnancy, on infection with different lineages of ZIKV.
Assuntos
Tolerância Imunológica , Receptores de Lipopolissacarídeos/imunologia , Monócitos/virologia , Complicações Infecciosas na Gravidez/imunologia , Infecção por Zika virus/imunologia , Zika virus/fisiologia , Adolescente , Adulto , Diferenciação Celular , Citocinas/sangue , Citocinas/imunologia , Feminino , Fibronectinas , Perfilação da Expressão Gênica , Interações Hospedeiro-Patógeno , Humanos , Imunidade Inata , Interferon Tipo I/imunologia , Macrófagos/virologia , Monócitos/fisiologia , Gravidez , Complicações Infecciosas na Gravidez/virologia , Transdução de Sinais , Adulto Jovem , Zika virus/genética , Zika virus/imunologia , Infecção por Zika virus/virologiaRESUMO
Linear ubiquitination is a newly discovered posttranslational modification that is currently restricted to a small number of known protein substrates. The linear ubiquitination assembly complex (LUBAC), consisting of HOIL-1L, HOIP, and Sharpin, has been reported to activate NF-κB-mediated transcription in response to receptor signaling by ligating linear ubiquitin chains to Nemo and Rip1. Despite recent advances, the detailed roles of LUBAC in immune cells remain elusive. We demonstrate a novel HOIL-1L function as an essential regulator of the activation of the NLRP3/ASC inflammasome in primary bone marrow-derived macrophages (BMDMs) independently of NF-κB activation. Mechanistically, HOIL-1L is required for assembly of the NLRP3/ASC inflammasome and the linear ubiquitination of ASC, which we identify as a novel LUBAC substrate. Consequently, we find that HOIL-1L(-/-) mice have reduced IL-1ß secretion in response to in vivo NLRP3 stimulation and survive lethal challenge with LPS. Together, these data demonstrate that linear ubiquitination is required for NLRP3 inflammasome activation, defining the molecular events of NLRP3 inflammasome activation and expanding the role of LUBAC as an innate immune regulator. Furthermore, our observation is clinically relevant because patients lacking HOIL-1L expression suffer from pyogenic bacterial immunodeficiency, providing a potential new therapeutic target for enhancing inflammation in immunodeficient patients.