Scientists have identified Rab35 which act as a switch mechanism controlling traffic in our body cells. Defects in this trafficking pathway can have severe consequences, leading to numerous diseases such as high cholesterol, neuropathies, sterility and complications in immune response. Understanding the mechanisms underlying these disorders is crucial to developing possible treatments and new therapeutic strategies.
Dr. Peter McPherson and Dr. Brigitte Ritter and their colleagues, have discovered how molecule Rab35, which acts as a switch is turned on in order to activate the fast-track recycling pathway - in which cargo that needs to be recycled back to the surface of the cell is rapidly selected and transported. The new study, published in the prestigious journal Molecular Cell, was conducted at The Montreal Neurological Institute and Hospital - The Neuro, McGill University.
In this study we identified that a particular region of the vesicle-bound protein connecden, , called the DENN domain, is the 'finger' that flips the switch, says Dr. Ritter.
DENN domains are found in multiple protein products encoded by 16 human genes. Mutations in the DENN domain cause humans diseases such as sterility and Charcot-Marie-Tooth neuropathy, yet until now the function of this common module has been unknown.
If the finger or the switch itself is mutated or missing, cargo can't recycle, which has dire consequences, adds Dr. McPherson. For example a very important cargo transported by this specific fast track recycling pathway, controlled by Rab35 is the MHC class I receptor involved in the immune system response. If a cell becomes infected by a virus, the MHC receptor is loaded with fragments of the virus that have infected the inside of a cell. The MHC receptor needs to be taken back to the cell surface quickly so that so that it can act as a signpost indicating to circulating immune cells that this particular cell has been infected by a virus and needs to be destroyed, preventing viral infection to other cells.
This critical new insight into the control mechanisms for the cells' trafficking system provide a deeper understanding of diseases that result from complications in trafficking, as well as provide new therapeutic targets for the development of treatments.