Two small GTPases interact with a protein implicated in osteopetrosis, to regulate cargo delivery to lysosomes
By Dr Mahak Sharma
This research was carried out in collaboration with Intermediate IA Fellow Dr Amit Tuli
Lysosomes are the recycling centers of a cell that digest extracellular and intracellular substrates including growth factor receptors, lipoproteins, damaged organelles and protein aggregates and recycle their constituents to build new proteins and membranes. Indeed, lysosomes play a vital role in maintaining cellular homeostasis reflected by more than 50 lysosomal storage disorders caused due to impaired degradation of substrates by lysosomes. Recent findings suggest that lysosome dysfunction is associated with more common human diseases as well, such as cancer, neurodegenerative disorders and obesity. In a collaborative study with India Alliance Intermediate Fellow, Dr Amit Tuli at CSIR-IMTECH (Chandigarh), we have now uncovered how two key GTP-binding proteins on lysosomes and late endosomes known as ARL8 and RAB7, respectively, coordinate their function to mediate cargo delivery to lysosomes. This is brought by the action of a common linker protein “PLEKHM1” that directly binds to both ARL8 and RAB7 and acts as a bridge to mediate fusion of endocytic and autophagic cargo vesicle with lysosomes.
Notably, mutations in PLEKHM1 gene result in the human disease Osteopetrosis, literally “stone bone”, where bones harden and lead to skeletal deformities. The underlying mechanism is defective bone absorption due to impaired lysosome secretion in the absence of PLEKHM1. However, little was known about how PLEKHM1 localizes to lysosomes or its function in controlling lysosome positioning. Our study reveals that ARL8 mediates PLEKHM1 lysosomal localization that in turn regulates ARL8–dependent lysosome positioning to the cell periphery. Our study significantly contributes to understanding of how lysosome transport and fusion with cargo vesicles is regulated that can lead to a better understanding of the mechanisms underlying lysosomes dysfunction.
The Rab7 effector PLEKHM1 binds Arl8b to promote cargo traffic to lysosomes. Rituraj Marwaha#, Subhash B. Arya#, Divya Jagga, Harmeet Kaur, Amit Tuli* and Mahak Sharma*. Journal of Cell Biology 2017 Mar 21. pii: jcb.201607085. doi: 10.1083/jcb.201607085. #equal contribution; *corresponding author