Novel insights into the regulation of Cellular Homeostasis


04 Jun 2015

Novel insights into the regulation of Cellular Homeostasis

Regulation of cargo trafficking to lysosomes- new insights into cellular homeostasis

By Dr Mahak Sharma

Intermediate Fellow, IISER Mohali

Lysosomes are membrane-bound compartments within cells of all eukaryotes that are dedicated to degradation of cellular cargo and recycling their contents to maintain the normal homeostasis of the cell. Several of these cargo molecules including signaling receptors or misfolded proteins if not degraded, can cause life-threatening diseases including cancer or neurodegenerative disorders. In this publication we have described the regulation of a key protein complex that resides on lysosomes and mediates delivery of cargo molecules to this recycling center of the cell. This protein complex known as HOmotypic Fusion and Protein Sorting (HOPS) complex is formed by six proteins that are conserved from yeast to humans. In this Journal of Cell Science publication, we have identified for the first time, how the human HOPS complex is targeted to lysosomes and how this regulates function of this protein complex in trafficking. Our findings indicate that HOPS complex regulates destruction of epidermal growth factor receptor (EGFR) in lysosomes. EGFR is a potent cancer-causing gene (oncogene) that drives tumor progression. Further, it is known that HOPS complex is required for the clearance of misfolded proteins associated with Parkinson’s disease. We find that a previously-reported variant of HOPS protein, present in a small percentage of the human population, cannot bind to lysosomes. It will be important to study if this population has a higher risk of diseases including Parkinson’s and cancer that can be caused due to interference with functions of lysosome.

The small GTPase Arl8b regulates assembly of the mammalian HOPS complex on lysosomes. Khatter D, Raina VB, Dwivedi D, Sindhwani A, Bahl S, Sharma M. J Cell Sci. 2015 May 1;128(9):1746-61. doi: 10.1242/jcs.162651. Epub 2015 Apr 23.

Link to the paper: http://www.ncbi.nlm.nih.gov/pubmed/25908847

Image: HOPS subunits colocalize with small GTPase Arl8b on lysosomes