Biology subjects

Matta, S. K.

Publications and source records attributed to Matta, S. K..

3 recordsLinked to original sources

bioRxiv2023

An intermembrane space protein facilitates completion of mitochondrial divisionin yeast

Mitochondria are highly dynamic double membrane-bound organelles that maintain their shape in part through fission and fusion. Mitochondrial fission is performed by the dynamin-related protein Dnm1 (Drp1 in humans), a large GTPase that constricts and divides the mitochondria in a GTP hydrolysis-dependent manner. However, it is unclear whether factors inside mitochondria help coordinate the process and if Dnm1/Drp1 activity alone is sufficient to complete fission of both mitochondrial membranes. Here, we identify an intermembrane space protein required for mitochondrial fission in yeast, which we propose to name Mdi1. Loss of Mdi1 leads to hyper-fused mitochondria networks due to defects in mitochondrial fission, but not lack of Dnm1 recruitment to mitochondria. Mdi1 plays a conserved role in fungal species and its homologs contain a putative amphipathic -helix, mutations in which disrupt mitochondrial morphology. One model to explain these findings is that Mdi1 associates with and distorts the mitochondrial inner membrane to enable Dnm1 to robustly complete fission. Our work reveals that Dnm1 cannot efficiently divide mitochondria without the coordinated function of a protein that resides inside mitochondria.

cell biology↗

bioRxiv2022

Molecular Basis for Interferon-mediated Pathogen Restriction in Human Cells

To define novel mechanisms for cellular immunity to the intracellular pathogen Toxoplasma gondii, we performed a genome-wide CRISPR loss-of-function screen to provide an unbiased assessment of genes important for IFN-{gamma}-dependent growth restriction. We revealed a previously unknown role for the tumor suppressor NF2/Merlin for maximum induction of Interferon Stimulated Genes (ISG), which are positively regulated by the transcription factor IRF-1. We then performed an additional focused ISG-targeted CRISPR screen that identified the host E3 ubiquitin ligase RNF213 as essential for IFN-{gamma} mediated control of T. gondii. RNF213 mediated ubiquitination of targets on the parasite-containing vacuole and growth restriction in response to IFN-{gamma} in a variety of cell types, thus identifying a conserved factor that plays a prominent role in human cells. Surprisingly, growth inhibition did not require the autophagy protein ATG5, indicating that RNF213 initiates restriction independent of a non-canonical autophagy pathway that has previously been implicated in control of T. gondii. RNF213 was also important for control of unrelated intracellular pathogens in human cells treated with IFN, as shown here for Mycobacterium tuberculosis and Vesicular Stomatitis Virus. Collectively, our findings establish RNF213 as a critical component of cell-autonomous immunity to a broad spectrum of intracellular pathogens in human cells.

microbiology↗

bioRxiv2021

Over-expression Screen of Interferon-Stimulated Genes Identifies RARRES3 as a Restrictor of Toxoplasma gondii Infection

Toxoplasma gondii is an important human pathogen infecting an estimated 1 in 3 people worldwide. The cytokine interferon gamma (IFN{gamma}) is induced during infection and is critical for restricting T. gondii growth in human cells. Growth restriction is presumed to be due to the induction interferon stimulated genes (ISGs) that are upregulated to protect the host from infection. Although there are hundreds of ISGs induced by IFN{gamma}, their individual roles in restricting parasite growth in human cells remain somewhat elusive. To address this deficiency, we screened a library of 414 IFN{gamma} induced ISGs to identify factors that impact T. gondii infection in human cells. In addition to IRF1, which likely acts through induction of numerous downstream genes, we identified RARRES3 as a single factor that restricts T. gondii infection by inducing premature egress of the parasite in multiple human cell lines. Overall, while we successfully identified a novel IFN{gamma} induced factor restricting T. gondii infection, the limited number of ISGs capable of restricting T. gondii infection when individually expressed suggests that IFN{gamma} mediated immunity to T. gondii infection is a complex, multifactorial process.

microbiology↗