Hanna Michael G, Rodriguez Cruz Hely O, Fujise Kenshiro, Wu Yumei, Xu C Shan, Pang Song, Li Zhuonging, Monetti Mara, De Camilli Pietro
Department of Neuroscience, Yale University School of Medicine, New Haven, CT.
Department of Cell Biology, Yale University School of Medicine, New Haven, CT.
bioRxiv. 2025 Apr 3:2024.09.28.615015. doi: 10.1101/2024.09.28.615015.
Recent studies have identified a family of rod-shaped proteins thought to mediate lipid transfer at intracellular membrane contacts by a bridge-like mechanism. We show one such protein, bridge-like lipid transfer protein 3A (BLTP3A)/UHRF1BP1 binds VAMP7 vesicles via its C-terminal region and anchors them to lysosomes via its chorein domain containing N-terminal region to Rab7. Upon lysosome damage, BLTP3A-positive vesicles rapidly (within minutes) dissociate from lysosomes. Lysosome damage is known to activate the CASM (Conjugation of ATG8 to Single Membranes) pathway leading to lipidation and recruitment to lysosomes of mammalian ATG8 (mATG8) proteins. We find that this process drives the reassociation of BLTP3A with damaged lysosomes via an interaction of its LIR motif with mATG8 which coincides with a dissociation from the vesicles. Our findings reveal that BLTP3A is an effector of CASM, potentially as part of a mechanism to help repair or minimize lysosome damage.
最近的研究发现了一类杆状蛋白，它们被认为通过类似桥梁的机制在细胞内膜接触处介导脂质转移。我们发现一种这样的蛋白，即类桥脂质转移蛋白3A（BLTP3A）/UHRF1BP1，通过其C末端区域结合VAMP7囊泡，并通过其含N末端区域的chorein结构域将它们锚定到溶酶体上的Rab7。溶酶体受损时，BLTP3A阳性囊泡会迅速（在几分钟内）从溶酶体上解离。已知溶酶体损伤会激活CASM（ATG8与单膜的缀合）途径，导致哺乳动物ATG8（mATG8）蛋白的脂化并募集到溶酶体。我们发现这个过程通过其LIR基序与mATG8的相互作用驱动BLTP3A与受损溶酶体重新结合，这与从囊泡上解离同时发生。我们的研究结果表明，BLTP3A是CASM的效应器，可能是帮助修复或最小化溶酶体损伤机制的一部分。
