New insights into protein aggregation and clearance in cells: implications in cancer and neurodegeneration


17 Sep 2018

New insights into protein aggregation and clearance in cells: implications in cancer and neurodegeneration

 

By Dr. Santosh Chauhan, Intermediate Fellow

Institute of Life Sciences, Bhubaneswar

Misfolded proteins are a common outcome of protein synthesis in the cells of our body. Normally, these misfolded proteins are degraded by the proteasome system and/or the autophagy process inside the cell. Multiple factors ranging from genetic mutations (in neurodegeneration) to cellular (oxidative/proteotoxic stress) and environmental stresses can trigger protein misfolding overwhelming the cellular capacity to clear them. The resulting formation and accumulation of protein aggregates leads to cell death and is linked to many pathological conditions such as Alzheimer’s, Parkinson’s, and Amyotrophic Lateral Sclerosis (ALS).

On the flip side, cancer cells can degrade stress-induced protein aggregates by hijacking the protein quality control machinery; this alleviates the oxidative stress of cancer cells and is required for both its initiation and maintenance (Chen et al. 2017, Cell Reports).

Given the importance of the formation of protein aggregates from misfolded proteins and their subsequent degradation (in neurodegeneration and cancer), it is vital to understand the mechanism by which turnover of protein aggregates takes place in the cell. To date, the mechanism by which protein aggregates are formed and degraded in cells remains elusive.

We discovered a novel mechanism by which cells handle stress-induced protein aggregates turnover for their better survival. Two proteins namely, TRIM16 and NRF2, govern a protein machinery to regulate the process of protein aggregates formation. Subsequently, TRIM16 engages the autophagy machinery to degrade the protein aggregates. Thus, TRIM16 streamlines the process of stress-induced aggregate clearance and protects cells against oxidative/proteotoxic stress-induced toxicity. Therefore, pharmacological targeting of TRIM16 to increase its activity will be helpful in managing neurodegeneration. Additionally, the genetic knockout of TRIM16 in cancer cells cripples their capability to handle oxidative stress or oncogenic stress leading to significant reduction in tumour size.

Thus, pharmacological targeting of TRIM16 to decrease its activity will be useful in cancer therapy.

Reference

TRIM16 controls assembly and degradation of protein aggregates by modulating the p62-NRF2 axis and autophagy. Jena KK, Kolapalli SP, Mehto S, Nath P, Das B, Sahoo PK, Ahad A, Syed GH, Raghav SK, Senapati S, Chauhan S, Chauhan S*.The EMBO Journal. August 2018.

* Corresponding authors

Banner image: Dr. Santosh Chauhan. Stress-induced protein aggregates and their disposal.

Press coverage: Drug target for neurodegenerative diseases and cancer discovered. The Hindu. 1 September 2018