Cell Biology and Gene Expression Section, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892.
Mol Biol Cell. 2022 Nov 1;33(13):ar124. doi: 10.1091/mbc.E22-04-0139. Epub 2022 Aug 31.
Lysosomes are dynamic organelles that can remodel their membrane as an adaptive response to various cell signaling events including membrane damage. Recently, we have discovered that damaged lysosomes form and sort tubules into moving vesicles. We named this process LYTL for LYsosomal Tubulation/sorting driven by LRRK2, as the Parkinson's disease protein LRRK2 promotes tubulation by recruiting the motor adaptor protein JIP4 to lysosomes via phosphorylated RAB proteins. Here we use spinning-disk microscopy combined with superresolution to further characterize LYTL after membrane damage with LLOMe (l-leucyl-l-leucine methyl ester). We identified the endoplasmic reticulum (ER) colocalizing with sites of fission of lysosome-derived tubules. In addition, modifying the morphology of the ER by reducing ER tubules leads to a decrease in LYTL sorting, suggesting that contact with tubular ER is necessary for lysosomal membrane sorting. Given the central roles of LRRK2 and lysosomal biology in Parkinson's disease, these discoveries are likely relevant to disease pathology and highlight interactions between organelles in this model.
溶酶体是动态细胞器，能够重塑其膜，作为对包括膜损伤在内的各种细胞信号事件的适应性反应。最近，我们发现受损的溶酶体形成并将小管分拣到移动的小泡中。我们将这个过程命名为 LYTL，即溶酶体管状化/分拣由 LRRK2 驱动，因为帕金森病蛋白 LRRK2 通过募集马达衔接蛋白 JIP4 到溶酶体，通过磷酸化 RAB 蛋白来促进管状化。在这里，我们使用旋转盘显微镜结合超分辨率技术，在 LLOMe（亮氨酰亮氨酸甲酯）处理后进一步研究溶酶体衍生小管分裂部位的 LYTL。我们鉴定了与溶酶体衍生小管分裂部位共定位的内质网 (ER)。此外，通过减少 ER 小管来修饰 ER 的形态会导致 LYTL 分拣减少，这表明与管状 ER 的接触对于溶酶体膜分拣是必要的。鉴于 LRRK2 和溶酶体生物学在帕金森病中的核心作用，这些发现可能与疾病病理学有关，并强调了该模型中细胞器之间的相互作用。
