Mechanistic information on the process of cellular waste clearance and novel therapeutics targeting this cellular machinery


01 Mar 2018

Mechanistic information on the process of cellular waste clearance and novel therapeutics targeting this cellular machinery

 

By Dr. Ravi Manjithaya, Intermediate Fellow

Jawaharlal Nehru Centre for Advanced Scientific Research, Bengaluru

Recently published research from our lab adds to our understanding of autophagy, the process of cleaning unwanted junk from the cell. Additionally, our research has identified novel drugs that target autophagy pathways and will now be tested in clinically-relevant systems.

Every cell in our body is equipped with housekeeping ability. The machinery used by the cell to bring about this is called autophagy. The process of autophagy helps the cell to respond to different physical and chemical stimuli by maintaining a constant internal environment. This is brought about by degradation of damaged or surplus proteins or organelles, eliminating invading bacterial pathogens and any dysfunctional protein by autophagy. Accumulation of toxic waste inside cell can lead to cancer, Alzheimer, Parkinson’s and other neurodegenerative disorders. The connection between several disease conditions and autophagy makes the process a target for genetic or pharmacological modulation and of current research interest.

Normally in a cell, the autophagy process functions at a low level and thus, it becomes very difficult to study it under laboratory conditions. We, therefore, need to externally add or remove certain components required by the cell to induce autophagy to a level of detection. We used nutrient starvation as means to induce it. We found out that a protein complex called septin, which is involved in cell division or cytokinesis, has a role in autophagy. When cells are deprived of nutrients, it does not undergo cytokinesis. Thus, when cell division does not happen, cell does not use the septin proteins for its division. But to preserve energy it utilizes septin for some other purpose. Our research found that under such conditions, septins help in formation of a structure called autophagosome that collects garbage and thus help autophagy process (1).

Further studies about how septins help in the formation of autophagosomes and how they collect the garbage inside the cell would shed light on the autophagy process and its modulation. This knowledge can be used to target autophagy process in a context of a disease.

Additionally, we developed a novel technique to study and screen for molecules that can modulate the process of autophagy (2). This study in a yeast model system provided us with potential drug candidates that we have further characterized in human cells which can now be used in an autophagy-dependent clinically-relevant system. Also, with the help of chemical modulators of autophagy, we have identified an autophagy like pathway in a hitherto unknown plant system, Aponogeton madagascariensis.

 
Figure: Arrested intermediates of autophagic flux through the action of small molecule modulators highlight autophagy to be a conserved process across three kingdoms. The figure depicts inhibition in autophagic flux by the action of small molecules in yeast, animal and plant cells. The double membrane structure, representative of autophagy is central to all eukaryotes. Different kingdoms are separated through a phylogenetic tree, depicting the evolutionarily conserved nature of autophagy.

Reference

1. Septins are involved at the early stages of macroautophagy in S. cerevisiae. Barve G, Sridhar S, Aher A, Sahani MH, Chinchwadkar S, Singh S, Lakshmeesha KN, McMurray MA, Manjithaya R. Journal of Cell Science. Jan 2018. 

This work was presented as a short talk at the EMBO conference on Molecular and cellular biology of septins held in Berlin, Germany (October 8-11, 2017). The summary of this meeting is now published in JCS.

https://meetings.embo.org/event/17-septins

First author Gaurav Barve’s interview in JCS
https://jcs.biologists.org/content/131/4/jcs216606.full

Meeting report – shining light on septins - https://jcs.biologists.org/content/131/1/jcs213702

2. Discovery of pan autophagy inhibitors through a high-throughput screen highlights macroautophagy as an evolutionarily conserved process across 3 eukaryotic kingdoms. Piyush Mishra, Adrian N. Dauphinee, Carl Ward, Sovan Sarkar, Arunika H.L.A.N. Gunawardena & Ravi Manjithaya. Autophagy. August 2017.

This work was presented as a short talk and poster in the Keystone Symposia Conference on ‘Autophagy network integration in health and disease’ held in Colorado, USA (February 12-16, 2017).
https://www.keystonesymposia.org/17B2