Characterization of TMEM251 that causes a new type of severe lysosome storage disease
Characterization of TMEM251 that causes a new type of severe lysosome storage disease
批准号:
10502880
负责人:
Ming Li
金额:
$43.24万
依托单位国家:
美国
项目类别:
财政年份:
2022
资助国家:
美国
项目状态:
未结题
起止时间:
2022-09-15 至 2027-08-31
关键词:
AddressAffectAutophagocytosisBindingBiogenesisBone DevelopmentCardiac EdemaCardiomegalyCell physiologyCessation of lifeChild DevelopmentChild HealthClustered Regularly Interspaced Short Palindromic RepeatsComparative StudyComplexDataDefectDevelopmentDiseaseDown-RegulationEndocytic VesicleEndocytosisEnzymesFunctional disorderGenesGolgi ApparatusHeart AbnormalitiesHumanHuman PathologyI-Cell DiseaseImpairmentIntegral Membrane ProteinJournalsKnock-outLabelLightLysosomal Storage DiseasesLysosomesMapsMass Spectrum AnalysisMembraneMembrane ProteinsMetabolismModificationMolecularMutationN-acetylglucopyranosylamineNutrientOrganellesPaperPathway interactionsPatientsPhosphotransferasesPlasmaReportingResearchRoleSignal TransductionSorting - Cell MovementTFE3 geneTailTestingTextUp-RegulationVertebratesZebrafishcardiogenesisearly childhoodgenome-widein vivolysosome membranemannose 6 phosphatemutantskeletal dysplasiatraffickingtranscriptome sequencingtreatment strategy
中文摘要
溶酶体是回收由内吞作用输送的物质的重要细胞器。
自噬。影响溶酶体的先天遗传缺陷会导致衰弱和致命的溶酶体
储藏性疾病(LSD,人类约70例)。LSD的一种严重形式,i-细胞疾病,会导致
骨骼发育不良,身材矮小,心脏肥大,并在第一个十年死亡。是由以下原因引起的
GlcNAc-1-磷酸转移酶(GNPT)的突变,作用于顺式-1-磷酸转移酶。
高尔基体用分选信号甘露糖-6-磷酸(M6P)标记溶酶体酶。丢失M6P
导致大多数溶酶体酶的分泌和有缺陷的溶酶体。2021年初,一个
报道了一种类似于I-细胞病的新型重度LSD。患者会发展成骨骼
发育不良,身材矮小,心脏缺陷,有些人在儿童早期死亡。它们的溶酶体
酶也会分泌到血浆中。它是由TMEM251的突变引起的,但
TMEM251的细胞功能和致病分子机制尚不清楚
地址。
在全基因组CRISPR基因敲除筛选中确定对降解至关重要的基因
人溶酶体膜蛋白,我们独立发现TMEM251是必需的
用于溶酶体功能。敲除TM251导致溶酶体功能障碍,原因是分泌
未经处理的溶酶体酶。因此,溶酶体积累了大量的
未消化的物质,如自噬小体和内吞小泡。与人类一致
在病理学上,敲除斑马鱼中的TM251会导致心脏缺陷和骨骼发育不良。
我们推测TM251在溶酶体酶的M6P生物发生途径中发挥作用。
我们将追求三个特定的目标来表征TM251在溶酶体生物发生中的作用。在……里面
目的1、研究TM251的膜拓扑结构、定位和寡聚化。在……里面
目的2,我们将剖析TM251与GNPT复合体在细胞内的关系
和生物体水平。在目标3中,我们将研究导致溶酶体的信号级联。
TM251基因敲除后上调。我们的发现将揭示TM251在M6P中的作用
并为一种新的溶酶体储存疾病提供了分子机制
严重影响儿童健康。
英文摘要
The lysosome is an essential organelle to recycle materials delivered by endocytosis and
autophagy. Inborn genetic defects affecting the lysosome cause debilitating and fatal lysosomal
storage diseases (LSDs, ~70 in humans). One severe form of LSD, the I-cell disease, leads to
skeletal dysplasia, short stature, cardiomegaly, and death in the first decade. It is caused by
mutations in the GlcNAc-1-phosphotransferase enzyme (GNPT), which functions at the cis-
Golgi to label lysosome enzymes with sorting signal mannose-6-phosphate (M6P). Missing M6P
leads to the secretion of most lysosomal enzymes and defective lysosomes. In early 2021, a
new type of severe LSD similar to the I-cell disease was reported. Patients will develop skeletal
dysplasia, short stature, cardiac defects, and some die in early childhood. Their lysosomal
enzymes are also secreted into the plasma. It is caused by mutations in TMEM251, but the
cellular function of TMEM251 and the molecular mechanism for the disease remain to be
addressed.
In a genome-wide CRISPR knockout screen to identify genes critical for the degradation of
human lysosome membrane proteins, we independently discovered TMEM251 to be essential
for lysosome function. Knocking out TM251 leads to lysosomal dysfunction due to the secretion
of unprocessed lysosomal enzymes. Consequently, lysosomes accumulate numerous
undigested materials such as autophagic bodies and endocytic vesicles. Consistent with human
pathology, knocking out TM251 in Zebrafish leads to cardiac defects and skeletal dysplasia.
We hypothesize that TM251 functions in the M6P biogenesis pathway of lysosomal enzymes.
We will pursue three specific aims to characterize the role of TM251 in lysosome biogenesis. In
aim 1, we will characterize membrane topology, localization, and oligomerization of TM251. In
aim 2, we will dissect the relationship between TM251 and the GNPT complex at both cellular
and organismal levels. In aim 3, we will study the signaling cascade that leads to lysosome
upregulation after knocking out TM251. Our findings will uncover the role of TM251 in the M6P
biogenesis and provide a molecular mechanism for a new lysosome storage disease that
severely affects child health.
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