Protein-Packed Menu for Blood Cells, Spiced with microRNAs
Work done in the lab of Dr. Lolitika Mandal at Indian Institute of Science Education and Research Mohali
Sushmit Ghosh is a PhD student at IISER Mohali working with Dr. Lolitika Mandal in the Department of Biological Sciences. Sushmit has completed his Bachelors in Zoology (Hons) from Shivaji College, University of Delhi. He then did his Masters in Forensic Sciences from National Forensic Science University, Delhi, followed by a Masters in Genetics at University of Delhi South Campus. Currently, at Dr. Mandal’s lab in IISER Mohali, he is interested in “RNA-related studies in the hematopoietic system of Drosophila melanogaster”.
Author Interview
How would you explain your research outcomes to the non-scientific community?
To put it simply, my team, under Dr. Lolitika Mandal’s supervision at IISER Mohali, have uncovered an ancient mechanism, well-preserved from our evolutionary ancestors, dating back to when we evolved from tiny organisms like fruit flies. We discovered that this ancient mechanism is still active in human blood. Most people in this modern day and age understand the importance of blood. As the central component of the animal circulatory system, blood is a liquid primarily composed of cells and protein-rich fluids, serving as a vital medium for bodily communication. Blood is widely recognized for transporting oxygen from the lungs and removing carbon dioxide, transporting essential nutrients and hormones, protecting against invading pathogens, etc. Therefore, the body constantly needs blood cells daily. Hence, they tend to grow and multiply immensely.
Growth and multiplication of anything requires nutrition. Among these nutrients, the requirement for proteins is indispensable for blood cell growth. Proteins (polymer of amino acids) are one of the key players in our study. We identify the ability of “Blood cell precursors” to sense an amino acid called “Leucine,” which in turn controls blood growth and multiplication. “Blood cell precursor” is a stage of a blood cell, where they grow and multiply before becoming many different kinds of blood cells that can carry oxygen, neutralize pathogens, etc. Specifically, our study shows how Leucine affects blood growth by controlling the degradation of small Ribonucleic Acids (RNAs) found in all cells, called micro-RNAs (miRNAs).
“RNA” is quite similar to but different from its famous counterpart “DNA.” However, in a cell, it is available in various shapes and sizes (mRNA, tRNA, rRNA, miRNA, etc.). Micro-RNAs (miRNA) are a special kind of RNA that harbour the ability to inhibit mRNA function. Messenger RNA (mRNA), on the other hand, is a central component of life. It is formed from DNA (genes) and contains a code language understood by cells to block-by-block construct new proteins in them. In an interesting turn of events, we found that under the influence of Leucine, miRNAs interacting with an mRNA behave differently in blood precursors. Instead of blocking mRNA’s code reading ability, miRNAs take mRNAs to the cell’s digestive compartments, named “Autophagosomes”. “Autophagy” (Auto=Self, Phagy = eating) is a process in cells where components inside a cell that need to be removed are digested into more usable forms. Autophagy occurs in special compartments named autophagosomes, which contain digestive enzymes and low pH regulators similar to our stomach.
The discovery and importance of autophagy have turned out to be very significant and relevant in biology, leading to a Nobel Prize in 2016. Autophagy is now understood to be important in many diseases and biological processes, thereby being heavily targeted for medical therapy. Until now, miRNA, despite being a key controller of almost all processes taking place in a cell, was not known as a delicacy in the menu list for autophagosomes. We, for the first time, found this blood-based mechanism in the fruit fly, which is proving to be an excellent model to study blood cells. However, as all scientists strive for, we also wanted to seek the broader importance of our findings. Therefore, our team went a step further and tested the validity of this mechanism in human blood precursors, where it turned out that not only was this mechanism present, but it also employed the same machinery similar to what we found in fruit flies. Therefore, our study again demonstrates that by using these tiny but simple fruit flies, we can decipher relevant mechanisms that were missed in the complex environment of human cells.
“The findings from this research widen the scope of miRNA-based targeting of cellular RNAs.”
How do these findings contribute to your research area?
The findings from this research widen the scope of miRNA-based targeting of cellular RNAs. So far, in any eukaryotic cell, miRNAs are not known to be targeted by autophagy-based degradation. We, for the first time, provide evidence of where such a process takes place. So far, miRNAs in animal cells are known to bind mRNA only and destabilize the translation machinery. Our research demonstrates an irreversible form of miRNA-based regulation, where the miRNA-bound mRNA is directed towards degradation in “Autophagosomes”; the miRNA-based degradation of mRNA in animal cells was not known previously. One of the most important implications that our work opens up in the foreseeable future is the possibility of miRNAs targeting “non-coding RNAs” that do not have a translation machinery on them for miRNA to impose its regulatory activity. Lastly, we demonstrate in an evidence-based manner that Drosophila blood precursors are similar to human myeloid precursors based on the functional axis of nutrient utilization and their control over miRNA-based machinery.
What was the exciting moment during your research?
I fondly recall that the most exciting moment of my research was when I found myself bored due to the unavailability of reagents immediately after COVID-19. Feeling a bit mischievous, I decided to experiment by feeding my Drosophila larvae various food variants, one of which was the protein powder commonly used as a health supplement by athletes and bodybuilders. To my surprise, I discovered that the protein powder significantly altered my experimental results. This unexpected finding sparked a deep curiosity in me and ultimately became the key discovery of my research article.
What do you hope to do next?
Micro-RNAs are at the forefront of gene regulation. In the context of RNA-based gene regulation, I find Dr. Carl Sagan’s words deeply resonant: “Somewhere, something incredible is waiting to be known.” I am committed to exploring interesting forms of cellular and molecular mechanisms, which are pivotal in enhancing vital biological concepts. Building on these novel aspects, I plan to progressively shift towards translational research that harbours significant biomedical value.
Where do you seek scientific inspiration from?
I draw my scientific inspiration from my mentors, colleagues, and their remarkable work, which I regularly read about. Delving into the historical perspectives documented in textbooks and captivating scientific novels by authors like Siddhartha Mukherjee and Richard Dawkins continually reignites my passion for science. However, the core of my scientific inspiration originates from the lessons I learned in the Genetics department, where I was taught to truly understand the essence of scientific investigation. Additionally, platforms like YouTube enable me to not only revisit interviews, ideas, and lectures from all my mentors but also to explore content from leading researchers worldwide. All these forms of exposure fuel my creativity and stroke my scientific curiosity.
How do you intend to help Indian science improve?
The development of technologies like CRISPR, Gene therapy, CAR-T cell therapies, etc. are excellent examples that demonstrate innovation in cell and molecular biology. They can have wonderful consequences for human betterment. India’s scientific landscape is currently undergoing a significant transformation, particularly in biological sciences. Our nation boasts a robust and technologically adept workforce excelling in various scientific domains. Looking ahead, my focus is on fundamental cellular and molecular studies that could lead to the development of innovative, cost-effective technologies with vast potential in gene therapy and biomedical therapeutics. Additionally, I aim to enter the education system so that I can contribute to skill development in molecular biology and cellular technology to help address the existing skill gap in our country, and significantly enhance India’s standing in molecular and cellular sciences.
Reference:
Sushmit Ghosh, Sreemoyee Chakraborti, Devki Devi, Rajesh Sahu, Sudip Mandal, Lolitika Mandal, A conserved nutrient responsive axis mediates autophagic degradation of miRNA–mRNA hybrids in blood cell progenitors, Nucleic Acids Research, 2023;, gkad1047, https://doi.org/10.1093/nar/gkad1047
Edited by: Ritvi Shah
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