Lysosomal trafficking, antigen presentation, and microbial killing are controlled by the Arf-like GTPase Arl8b.
Lysosomal trafficking, antigen presentation, and microbial killing are controlled by the Arf-like GTPase Arl8b.
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DOI：
10.1016/j.immuni.2011.06.009
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发表时间：
2011-08-26
期刊：
影响因子：
32.4
通讯作者：
Brenner MB
中科院分区：
文献类型：
--
作者：
Garg S;Sharma M;Ung C;Tuli A;Barral DC;Hava DL;Veerapen N;Besra GS;Hacohen N;Brenner MB
抗原呈递和微生物杀伤是宿主防御的关键武器，依赖于货物运输到溶酶体中。然而，人们对进入溶酶体的分子调节剂仅部分了解。在这里，使用运输shRNA文库的溶酶体依赖性免疫学筛选，我们鉴定了Arf样GTdR Arl8b作为向溶酶体递送货物的关键调节剂。同型融合和液泡蛋白分选（HOPS）复合物成员被鉴定为Arl8b的效应物，并且依赖于Arl8b募集到溶酶体，表明Arl8b-HOPS在引导运输到溶酶体中起一般作用。此外，在Arl8b沉默的细胞中，溶酶体中CD 1抗原呈递复合物的形成、它们向质膜的递送以及吞噬体-溶酶体融合都显著受损，导致T细胞活化和微生物杀伤的相应缺陷。总之，这些结果将Arl8b定义为溶酶体细胞和免疫功能的关键调节剂。EAR18b沉默减少溶酶体CD1d抗原呈递给NKT细胞EAR18b控制内吞葡聚糖、LDL和CD1d向溶酶体的运输EAR18b结合VPS41并将HOPS复合物成员募集到溶酶体EAR18b控制吞噬体向溶酶体的运输和微生物杀伤
Antigen presentation and microbial killing are critical arms of host defense that depend upon cargo trafficking into lysosomes. Yet, the molecular regulators of traffic into lysosomes are only partly understood. Here, using a lysosome-dependent immunological screen of a trafficking shRNA library, we identified the Arf-like GTPase Arl8b as a critical regulator of cargo delivery to lysosomes. Homotypic fusion and vacuole protein sorting (HOPS) complex members were identified as effectors of Arl8b and were dependent on Arl8b for recruitment to lysosomes, suggesting that Arl8b-HOPS plays a general role in directing traffic to lysosomes. Moreover, the formation of CD1 antigen-presenting complexes in lysosomes, their delivery to the plasma membrane, and phagosome-lysosome fusion were all markedly impaired in Arl8b silenced cells resulting in corresponding defects in T cell activation and microbial killing. Together, these results define Arl8b as a key regulator of lysosomal cellular and immunological functions. ► Arl8b silencing reduces lysosomal CD1d antigen presentation to NKT-cells ► Arl8b controls trafficking of endocytosed dextran, LDL, and CD1d to lysosomes ► Arl8b binds VPS41 and recruits HOPS Complex members to lysosomes ► Arl8b controls phagosome to lysosome trafficking and microbial killing
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影响因子：
2.7
作者：
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