First author interview: Mr. Sourav Ghosh was born and raised in Kolkata. He completed his bachelor’s in Biochemistry from Vidyasagar College, University of Calcutta, and his Master’s in Biochemistry from the Ballygunge Science College, University of Calcutta. In 2019, he joined and is still pursuing his Ph.D. at the Bacterial Pathogenesis lab under the supervision of Prof. Anirban Banerjee at the Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay. His research explores the various aspects of cellular immunity in eukaryotic cells.
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Lab: Prof. Anirban Banerjee, Indian Institute of Technology Bombay
Research Summary: Bacterial pathogens enter cells to steal nutrients and spread, but cells fight back by tagging them with a death tag, ‘Ubiquitin’, and unleashing a tiny machine, VCP/p97, to destroy them.
What was the core problem you aimed to solve with this research?
Our research addresses two core problems. First, at the broader level, we explored how host cells defend their cytosol against invading pathogens. Unlike many well-studied defenses that target specific pathogens, we believed that for better protection, the cytosol must have evolved a general, all-purpose immune strategy. Our study uncovers one such mechanism, where ubiquitination of diverse pathogens activates a molecular tweezer, the AAA-ATPase, VCP/p97, which helps extract bacterial components and eliminate the infection.
Second, at the molecular level, we tackled a paradox. Ubiquitinated bacteria recruit the proteasome, yet the proteasome is too small to degrade an entire bacterium. We found that this AAA-ATPase, VCP/p97, acts as an auxiliary factor to extract ubiquitinated bacterial proteins. This allows stepwise plucking out of bacterial components, rupturing the pathogen and compromising its viability, explaining how ubiquitin tags become lethal.
How did you go about solving this problem?
Our research was highly multidisciplinary, requiring the problem to be addressed from multiple perspectives. We were fortunate to have supportive collaborators who contributed a range of complementary experiments to tackle the question. Alongside standard cell-based and biochemical assays, as well as a murine sepsis model, we developed an in-vitro reconstitution system using fully purified proteins to directly assess the antibacterial role of p97. To visualize its interaction with bacteria, we employed super-resolution microscopy along with 3D reconstruction. Additionally, molecular dynamic simulation and optical trapping assay were done with the help of our collaborators to reveal the tweezer-like mechanism of p97 in extracting bacterial proteins. This diverse approach allowed us to connect molecular mechanisms with the bigger picture, i.e., host defense.
Our cells are clever, but so are bacteria, both evolving and crafting new ways to outsmart each other. In this fight for survival, our work unravels the role of human AAA-ATPase, VCP/p97, as a defense strategy, exploiting this mechanism could potentially tip the balance of this war in our favor.
How would you explain your research outcomes (Key findings) to the non-scientific community?
At every given moment, we are exposed to countless germs, yet we rarely fall sick, thanks to our immune system’s constant protection. Our research reveals how human cells defend themselves when harmful bacteria manage to sneak inside. Cells mark these dangerous bacteria with ubiquitin, like a ‘red flag’. But tagging alone isn’t enough, the cell then calls in the tiny plucking machine. These machines are proteins that surround the flagged bacteria and begin removing its parts, much like a swarm of piranhas biting their prey piece by piece. This kills the microbe and stops the infection.
What are the potential implications of your findings for the field and society?
Our findings reveal that human cells are not just passive victims when bacteria sneak in, but they fight back with clever tricks. We uncovered a general defense system, which is the cell’s way of saying, ‘If you break in, we will break you.” Through this broad-spectrum mechanism, we hope to open the door to novel strategies that could help us outsmart the infection and even if it never leads to a drug, we hope it will at least be a cool and exciting story to read for the scientific community.
What was the exciting moment during your research?
The most exciting part of this project was the collaboration. It was not just about the discovery but the entire journey. There were numerous challenges, traveling to different institutes to capture high-quality microscopic images, experimenting with various new systems, and the incredible teamwork displayed by my lab mates. My supervisor’s constant push for improvement was invaluable, and along the way, I made amazing friends. Research can be daunting, but beyond the struggle, the amount I have learned is unparalleled. While the discovery is thrilling, it’s really the process, the teamwork, the challenges, and the learning that made this experience so rewarding.
Reference: Ghosh S et al. Host AAA-ATPase VCP/p97 lyses ubiquitinated intracellular bacteria as an innate antimicrobial defence. Nature Microbiology (2025). https://doi.org/10.1038/s41564-025-01984-y
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