Low‐density lipoprotein receptor‐related protein 1 mediates α1‐antitrypsin internalization in CD4+ T lymphocytes

[摘要] Inα1‐antitrypsin–deficientHIVpatients,anaccelerateddeclineofCD4+Tcellnumbersisobserved,suggestingthatα1‐antitrypsinisapotentialendogenousHIVinhibitor.IninfectedTlymphocytes,α1‐antitrypsinpotentlyblocksNF‐κBactivationandHIV‐1replicationbydirectlyinteractingwithIκBαinthecytosol,therebyalteringitsubiquitinationpattern.However,themechanismofα1‐antitrypsinentryintothecytosol,whereIκBαlocates,remainsunclear.Inthepresentstudy,weinvestigatedthemechanismofα1‐antitrypsininternalizationinCD4+Tcells.Thus,primaryCD4+TcellswereinfectedwithHIV‐1andthenincubatedwithα1‐antitrypsintodetectitsinternalization.WefoundthatCD4+Tcellsinternalizedα1‐antitrypsinthroughaclathrin‐dependentendocytosisprocess.Next,intracellularα1‐antitrypsinexertedtheinhibitoryeffectonNF‐κBactivationandHIV‐1replication.OnprimaryCD4+Tcells,α1‐antitrypsininteractedwithlow‐densitylipoproteinreceptor‐relatedprotein1toinitiatetheinternalization.InsideCD4+Tlymphocytes,α1‐antitrypsinwastransportedfromtheendosometothelysosomeandthenreleasedintothecytosol,whereitispossibleforα1‐antitrypsintodirectlyinteractwithIκBα.Theseresultstogethersuggestthatα1‐antitrypsininternalizationisaclathrin‐dependentandlow‐densitylipoproteinreceptor‐relatedprotein1–mediatedendocytosisprocess.Internalizedα1‐antitrypsinistransportedthroughtheendosome–lysosome–cytosolroutinetointeractwithcytosolicIκBαandblockNF‐κBactivationandHIV‐1replication...

[学科分类] 生理学

[关键词] clathrin‐dependent endocytosis;endosome;lysosome;HIV‐1;NF‐κB;IκBα