Dr. Mahak Sharma Group Highlights
Dr. Mahak Sharma interview on "Cell Scientist to Watch Column"
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*
J Cell Biol. 2017 Apr 3;216(4):1051-1070. doi: 10.1083/jcb.201607085. Epub 2017 Mar 21.
#CSIR-IMTECH (Chandigarh) and *Department of Biological Sciences, IISER-Mohali
In a collaborative study with India alliance Intermediate fellow, Dr. Amit Tuli at CSIR-IMTECH, we have now uncovered how two key GTP-binding proteins on lysosomes and late endosomes known as ARL8 and RAB7 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 RAB7 and ARL8 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 lysosome dysfunction.
DQ-Red BSA Trafficking Assay in Cultured Cells to Assess Cargo Delivery to Lysosomes
Rituraj Marwaha and Mahak Sharma
Bio-protocol (Vol 7, Iss 19, October 05, 2017)
The small GTPase Arl8b regulates assembly of the mammalian HOPS complex to lysosomes.
Divya Khatter, Vivek B. Raina, Devashish Dwivedi, Aastha, Sindhwani, Surbhi Bahl and Mahak Sharma*.
J Cell Sci. 2015 May 1;128(9):1746-61.
HOmotypic Fusion and Protein Sorting (HOPS) complex is a six-subunit lysosomal protein complex that mediates fusion of endosomes, phagosomes or autophagosomes with lysosomes and is implicated in regulation of lysosome function in health and disease. In this publication, we have identified for the first time, how the human HOPS complex is targeted to lysosomes. HOPS complex binds to lysosomes by the action of the small GTP-binding protein, Arl8b. Interaction of Arl8b and HOPS regulates the function of this protein complex in degradation of epidermal growth factor receptor (EGFR) which encodes a potent cancer-causing gene (oncogene) that drives tumor progression.
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