LRRK2 activation controls the repair of damaged endomembranes in macrophages.
LRRK2 activation controls the repair of damaged endomembranes in macrophages.
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DOI：
10.15252/embj.2020104494
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发表时间：
2020-09-15
期刊：
影响因子：
--
通讯作者：
Gutierrez MG
中科院分区：
文献类型：
--
作者：
Herbst S;Campbell P;Harvey J;Bernard EM;Papayannopoulos V;Wood NW;Morris HR;Gutierrez MG
细胞对内溶酶体损伤的反应要么是修复损伤，要么是通过溶噬来降解受损的内溶酶体。然而，调节修复或溶体吞噬决定的信号没有得到很好的表征。在这里，我们发现帕金森病（PD）相关的激酶LRRK2在巨噬细胞中被病原体或无菌诱导的内膜损伤激活。LRRK2招募Rab GTPase Rab8A到受损的内溶酶体以及ESCRT‐III成分CHMP4B，从而有利于ESCRT‐介导的修复。相反，在缺乏LRRK2和Rab8A的情况下，受损的内溶酶体被靶向溶噬。这些观察结果在PD患者的巨噬细胞中得到了概括，其中致病性LRRK2功能增益突变导致内溶酶体的积累，而内溶酶体对膜损伤标志物凝集素- 3呈阳性。总之，本研究表明LRRK2通过控制膜修复和细胞器替换之间的平衡来调节内溶酶体稳态，揭示了LRRK2意想不到的功能，并为膜损伤和PD之间提供了新的联系。Rab8A GTPase的LRRK2磷酸化促进其与ESCRT成分CHMP4B共易位到受损的内溶酶体进行修复。
Cells respond to endolysosome damage by either repairing the damage or targeting damaged endolysosomes for degradation via lysophagy. However, the signals regulating the decision for repair or lysophagy are poorly characterised. Here, we show that the Parkinson's disease (PD)‐related kinase LRRK2 is activated in macrophages by pathogen‐ or sterile‐induced endomembrane damage. LRRK2 recruits the Rab GTPase Rab8A to damaged endolysosomes as well as the ESCRT‐III component CHMP4B, thereby favouring ESCRT‐mediated repair. Conversely, in the absence of LRRK2 and Rab8A, damaged endolysosomes are targeted to lysophagy. These observations are recapitulated in macrophages from PD patients where pathogenic LRRK2 gain‐of‐function mutations result in the accumulation of endolysosomes which are positive for the membrane damage marker Galectin‐3. Altogether, this work indicates that LRRK2 regulates endolysosomal homeostasis by controlling the balance between membrane repair and organelle replacement, uncovering an unexpected function for LRRK2, and providing a new link between membrane damage and PD. LRRK2 phosphorylation of Rab8A GTPase promotes its co‐translocation with ESCRT component CHMP4B to damaged endolysosomes for their repair.
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DOI：
10.1126/science.aar5078
发表时间：
2018-04-06
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Skowyra ML;Schlesinger PH;Naismith TV;Hanson PI
通讯作者：
Hanson PI
影响因子：
4.2
作者：
Blauwendraat C;Faghri F;Pihlstrom L;Geiger JT;Elbaz A;Lesage S;Corvol JC;May P;Nicolas A;Abramzon Y;Murphy NA;Gibbs JR;Ryten M;Ferrari R;Bras J;Guerreiro R;Williams J;Sims R;Lubbe S;Hernandez DG;Mok KY;Robak L;Campbell RH;Rogaeva E;Traynor BJ;Chia R;Chung SJ;International Parkinson's Disease Genomics Consortium (IPDGC), COURAGE-PD Consortium;Hardy JA;Brice A;Wood NW;Houlden H;Shulman JM;Morris HR;Gasser T;Krüger R;Heutink P;Sharma M;Simón-Sánchez J;Nalls MA;Singleton AB;Scholz SW
通讯作者：
Scholz SW
影响因子：
6.7
作者：
Lopez-Jimenez, Ana T.;Cardenal-Munoz, Elena;Soldati, Thierry
通讯作者：
Soldati, Thierry
影响因子：
3.9
作者：
Manzoni C
通讯作者：
Manzoni C
DOI：
10.1126/science.1204592
发表时间：
2011-06-17
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Settembre C;Di Malta C;Polito VA;Garcia Arencibia M;Vetrini F;Erdin S;Erdin SU;Huynh T;Medina D;Colella P;Sardiello M;Rubinsztein DC;Ballabio A
通讯作者：
Ballabio A