A roundup of research articles published in the previous month (16 December 2022 – 15 January 2023) at the institute:
Research Spotlight : Search for a regulatory non-coding RNA
There seem to be shared proteins and interaction pathways between neurodevelopment, neuropsychiatric diseases and neurodegeneration. Kalirin is one such protein which plays a key role in the formation of dendritic spines, dendritic arborization, axonal growth, synapse formation, and neuronal plasticity. Dysfunction of the Kalirin protein has seen to be associated with diseases like autism, schizophrenia, intellectual disability, and AD. The human KALRN gene is known to have 60 exons and give rise to 50 plus isoforms. The huge number of isoforms explains how a single gene is mediating diverse functions and implicated in diverse neurological and neuropsychiatric conditions.
In this study, Beena Pillai’s lab reports the presence of various non-coding transcripts – lncRNAs and one circular RNA – that arise from the KALRN locus in the mammalian brain based on the analysis of the available genomic and transcriptomic data. In their previous studies, they reported a maternally inherited lncRNA, durga that arises from the KALRN locus in the zebrafish brain. In this article, they have identified putative durga like lncRNA arising from the 5’ end of the KALRN locus in mammals. This lncRNA was shown to downregulate the various protein coding transcripts of KALRN (in a mouse neuronal cell line). The implications of this regulatory mechanism are diverse and further studies will help in dissecting out the common/diverse pathways of neurodevelopment, neuropsychiatric diseases and neurodegeneration.
A Novel Cis-Regulatory lncRNA, Kalnc2, Downregulates Kalrn Protein-Coding Transcripts in Mouse Neuronal Cells
https://pubmed.ncbi.nlm.nih.gov/36649036/
Novel host-directed therapy for tuberculosis
The rise in multi-drug resistant strains of mycobacterium stresses upon the need for novel strategies for treating tuberculosis. Host directed therapy by targeting the host offers the advantage of being recalcitrant to pathogen meditated drug resistance.
Vivek Rao’s group show in this study that Sertraline, an FDA approved molecule belonging to the selective serotonin reuptake inhibitor (SSRI) class of antidepressants, can be repurposed for TB therapy. They showed that a combination of Sertraline with existing TB drugs was better effective in clearing the TB causing bacterium, from mice tissues. This novel adjunct therapy, by virtue of it offering faster bacterial clearance could be a significant help in fighting the TB pandemic in the country.
The antidepressant sertraline provides a novel host directed therapy module for augmenting TB therapy
https://elifesciences.org/articles/64834
AlphaFold and patatin like proteins
Lipids play an essential role in the survival and adaptation of Mycobacterium tuberculosis. The lipid metabolic pathways in mycobacterium have still to be uncovered. The large proportion of genes involved in lipid metabolism in the mycobacterium further points towards the need to understand their roles. The presence of certain lipases has been shown to act as virulence factors by providing a growth advantage and increased infectivity to the pathogenic species of bacteria.
Many bacterial proteins that have been shown to play an essential role in virulence share a patatin domain with Patatins, which were first described in potatoes. Patatin family proteins of mycobacterium have been shown to confer virulence to non-pathogenic species of mycobacterium. Sheetal Gandotra’s lab used AlphaFold structure prediction for patatin family proteins of mycobacterium. In this paper, they have predicted the regulation, membrane and substrate binding of these proteins. The structure prediction is going to further help in elucidating the functions of these proteins in lipid metabolism.
Structure prediction-based insights into the patatin family of Mycobacterium tuberculosis
https://www.microbiologyresearch.org/content/journal/micro/10.1099/mic.0.001270
Conformational flexibility of T. rubrum PacC
Dermatophytes are the fungi, which invade the outermost layer of skin and are responsible for causing athlete’s foot, ringworm, jock itch and other fungal infections in human and animals. A human infecting dermatophyte species Trichophyton rubrum causes 80-90% of superficial fungal infections. The survivability of this pathogen during the pH shift it encounters (i.e. from slightly acidic pH of human skin/ nail to alkaline pH) while causing an infection depends on PacC which is a major pH regulatory transcription factor.
To perform its function, PacC needs to be activated at alkaline pH by the proteloytic cleavage of its C terminal chain which is organism specific. In this study, Bhupesh Taneja’s lab characterized the structure of the C terminus chain of T. rubrum PacC. A combination of biophysical tools and bioinformatics analysis of the C terminus were carried out which indicated that the confromational flexibility of this C- terminus seems to be required for its function.
Biophysical Characterization of the C-Terminal Tail of T. rubrum PacC Reveals an Inherent Intrinsically Disordered Structure with pH-Induced Structural Plasticity
https://pubs.acs.org/doi/10.1021/acsomega.2c04691