JNCASR Finds Exocyst Complex Drives Autophagy, Opening New Therapeutic Pathways

Autophagy is the cellular equivalent of a housekeeping system. When operating correctly, it eliminates damaged proteins, toxic aggregates, worn-out mitochondria and pathogens.

In a breakthrough that redefines understanding of how cells clean themselves, researchers have discovered that the exocyst complex—a group of proteins best known for assisting in cellular secretion—plays a critical and previously unrecognized role in autophagy, the “self-eating” process that allows cells to remove damaged components, fight infections, and maintain long-term health.

The discovery, by scientists at the Jawaharlal Nehru Centre for Advanced Scientific Research (JNCASR), an autonomous institution under the Department of Science and Technology (DST), provides fundamental new insights into early steps of autophagosome biogenesis, a key stage in the autophagy pathway. Because defects in autophagy underlie several neurodegenerative diseases—including Alzheimer’s, Parkinson’s, and Huntington’s—as well as many cancers, the findings open the door to new therapeutic strategies aimed at restoring this essential cellular process.

Why Autophagy Matters: Keeping Neurons and Tissues Healthy

Autophagy is the cellular equivalent of a housekeeping system. When operating correctly, it eliminates damaged proteins, toxic aggregates, worn-out mitochondria and pathogens. When it malfunctions, cellular waste accumulates and health deteriorates—particularly in long-lived cells such as neurons, which cannot easily be replaced.

Autophagy has a dual identity in cancer:

• It prevents tumor initiation by maintaining genome stability and clearing harmful cellular debris.

• Yet in later stages, some cancer cells hijack autophagy to fuel their survival and proliferation.

Understanding how autophagy is initiated and regulated is therefore key to developing targeted therapies across a spectrum of diseases.

Exocyst Complex: From Cell Surface Transport to Autophagy Regulation

The JNCASR team, led by Prof. Ravi Manjithaya, found that seven of the eight proteins within the exocyst complex are essential for proper autophagosome formation. Normally, this complex helps deliver molecules to the cell’s outer membrane. The study revealed that it also helps “grow” the nascent membrane structure—the cell’s trash bag—that eventually wraps damaged material.

When components of the exocyst were missing:

• The autophagosome “bag-making” machinery stalled

• Cells produced faulty, non-functional intermediates

• Autophagy efficiency dropped dramatically

This identification of the exocyst as a key early-stage regulator of autophagy significantly broadens scientific understanding of how autophagosomes assemble.

Yeast as a Model: Simple Cells, Powerful Insights

Using yeast cells, which share essential autophagy genes with higher organisms, the researchers mapped how autophagosomes form and mature. Because yeast allows high-resolution genetic studies, the team could pinpoint exactly how the exocyst contributes to membrane expansion.

The findings demonstrate that mechanisms of autophagy initiation are deeply conserved, making this work directly relevant to human neurobiology and disease research.

Therapeutic Promise: Restoring Autophagy in Disease

Published in the Proceedings of the National Academy of Sciences (PNAS), the study provides a foundation for:

• Identifying drug targets that enhance or restore autophagy

• Correcting early autophagy defects in neurodegenerative disorders

• Preventing cancer cells from exploiting autophagy for growth

• Designing molecules to modulate autophagosome biogenesis

By revealing a completely new functional dimension of the exocyst complex, the work charts a pathway toward precision therapies aimed at rebalancing the cell’s internal waste-management system.

Publication: https://www.pnas.org/doi/10.1073/pnas.2426476122