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We study functional regulation of ribonucleoprotein condensates
Functional Regulation of Biomolecular Condensates
Functional Regulation of Biomolecular Condensates
A fundamental challenge in cell biology is to understand how biochemical reactions are organized and precisely regulated in space and time in the densely packed cellular microenvironment. One way cells achieve this specificity is by compartmentalization of the cellular space into subcellular compartments.
Besides the classical membrane bound organelles such as the nucleus, mitochondria, endoplasmic reticulum, there exists a repertoire of membraneless organelles including nucleolus, stress granules, germ granules and others, which are now considered to be biomolecular condensates. Condensates may form through the physical process of phase separation and are characterized by the ability to concentrate proteins and nucleic acids. The collective behavior of biomolecules within condensates confers emergent material properties which cells can harness to achieve specific cellular functions.
The Bose lab is interested in studying the molecular principles of assembly, function and regulation of membraneless RNA-protein assemblies primarily using the fruit fly germline development model.
Research Questions
Research Questions
Translation regulation in membraneless RNP granules
Translation regulation in membraneless RNP granules
Translation decodes the information in an mRNA to build a polypeptide. Despite basic knowledge of the process of translation, mechanistic understanding of in vivo translation dynamics and regulation is limited. In the developing fly oocyte, oskar mRNA is transported as RNA-protein condensates in a translationally repressed state and translational activation occurs after localization to the posterior pole. Therefore, oskar translation regulation is an ideal system to study spatial control of translation of mRNAs packaged in membraneless organelles.
The principles learnt can be extrapolated to other cellular condensates implicated in translation regulation such as neuronal RNP granules, stress granules and P-bodies.
Compositional control of biomolceular condensates
Compositional control of biomolceular condensates
Biomolecules absolutely essential for driving condensate assembly are 'scaffolds' whereas, those that partition into the condensate and regulate its functions are 'clients'. Client partitioning into pre-formed condensates can dynamically remodel the composition of biomolecular condensates in space and time which consequently can regulate their cellular function. In RNP granules, partitioning of cytoskeletal motor protein adaptors can regulate intracellular transport or selective partitioning of translation regulators can control the translation state of the mRNAs.
Identification and characterization of potential clients can elucidate not only their biological function in the condensate but also provide insights into the molecular principles of selective partitioning.
Regulation of functional material properties of RNP granules
Regulation of functional material properties of RNP granules
Biomolecular condensates span a spectrum of material properties from dynamic liquids to highly viscoelastic gels and glasses. Recent evidence confirm that their physical properties are tuned for their biological function. Additionally, pathogenic mutations in condensate proteins can lead to aberrant phase transitions or misregulation of phase separation that culminates to disease phenotypes including neurodegenerative diseases such as Amyotrophic Lateral Sclerosis (ALS), FrontoTemporal Dementia (FTD), etc.
Thus, condensate physical properties as well as intracellular phase transitions must be tightly regulated to maintain cellular homeostasis.
Role of cellular surfaces in condensate assembly
Role of cellular surfaces in condensate assembly
Two-dimensional cellular surfaces provide a platform where biomolecules can de-mix and undergo liquid-liquid phase separation at much lower critical concentrations than in solution.
Plasma membrane as well as organellar membranes can assist condensation to create assemblies with membrane-associated functions. Condensation of specific RNA-binding proteins on cytoskeletal filaments can lead to de novo assembly of transport RNP granules on cytoskeletal tracks.
Role of RNA-RNA interactions in RNP granule assembly
Role of RNA-RNA interactions in RNP granule assembly
RNAs are a major constituent of many essential cellular condensates, including stress granules, germ granules and neuronal transport granules1. While the field of biomolecular condensation has been gaining substantial understanding of the protein molecular grammar that governs phase separation and tunes physical properties of physiological or pathological condensates, little understanding exists on the contribution of RNA, its sequence- specific tertiary interactions v/s promiscuous base-pairing.
We dissect the mechanisms of sequence specific intermolecular RNA-RNA interactions in driving condensation and how RNA-RNA interactions coordinate with RNA-protein and protein-protein interactions to drive mesoscale assemblies in vivo.
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