Biology subjects

Potharaju, P. S.

Publications and source records attributed to Potharaju, P. S..

3 recordsLinked to original sources

bioRxiv2026

Cytosolic interaction with RNA-helicase DDX39A titrates viral RNA G-quadruplex mediated α-Synuclein amyloidogenesis

Amyloid aggregates of -Synuclein are hallmark of Parkinsons Disease (PD) and related neurodegenerative diseases. -Synuclein, being an non-canonical RNA-binding protein (RBP), associates with other RBPs within cytosolic RNA-protein granules to modulate mRNA-stability. Conversely, mRNA G-quadruplexes (rG4s) expedite -Synuclein amyloidogenesis. However, spatiotemporal control on -Synuclein amyloidogenesis by other RBPs remains unexplored. Here, we report that RNA-dependent cytosolic interaction with DEAD-box RNA-helicase DDX39A decelerates -Synuclein amyloidogenesis. Viral infections transiently elevate rG4s in cytoplasm. Perturbing interactions between Synuclein and DDX39A using viral rG4s from H1N1-influenza and SARS-CoV-2 genomes expedites intracellular amyloidogenesis. Conversely, DDX39A overexpression alleviates -Synuclein amyloidogenesis in mouse primary neurons triggered by SARS-CoV-2 infection. We demonstrate that while DDX39A unwinds viral rG4s to mitigate -Synuclein sol-gel transition, its reciprocal cooperative phase separation with -Synuclein enhances the helicases rG4-unwinding activity. We propose that accelerated -Synuclein amyloidogenesis represents a trade-off within this RNA-protein interaction equilibrium, contributing to the viral etiology of PD.

biochemistry↗

bioRxiv2025

MAVS Orchestrates a Potent IFN-independent Antiviral Immunity by Preserving Mitochondrial Integrity

Intrinsic antiviral defenses can restrict infection independent of paracrine interferon (IFN) signaling. While mitochondrial homeostasis is essential for immunity, its direct role in viral restriction remains incompletely understood. Here, we identify mitochondrial antiviral signaling protein (MAVS) as a central effector of a potent IFN-independent antiviral immunity orchestrated though mitochondrial safeguarding. We demonstrate that MAVS is critical for mitochondrial integrity as its loss leads to mitochondrial fragmentation, depolarization, and elevated mitophagy, alongside impaired bioenergetics and protein import. Mechanistically, MAVS maintains mitochondrial integrity by stabilizing the translocase of the outer membrane (TOM) complex and sustaining the abundance of its core components. Remarkably, this mitochondria-driven immunity restricts SARS-CoV-2 replication even under IFN-deficient conditions, and operates alongside the IFN pathways during JEV infection. Our findings redefine MAVS as a mitochondrial guardian that preserves organellar stability to enact host defense. These results highlight mitochondrial integrity as a fundamental determinant of broad antiviral immunity, integrating intrinsic and IFN-dependent mechanisms to counteract viral pathogenesis.

immunology↗

bioRxiv2022

SARS-CoV-2 Variant Delta Potently Suppresses Innate Immune Response and Evades Interferon-Activated Antiviral Responses

Delta variant of SARS-CoV-2 has caused more severe infections than its previous variants. We studied the host innate immune response to Delta, Alpha and two earlier variants to map the evolution of the recent ones. Our biochemical and transcriptomic studies reveal that Alpha and Delta have progressively evolved over the ancestral variants by silencing innate immune response, thereby limiting cytokine and chemokine production. Though Alpha silenced RLR pathway just as Delta, it failed to persistently silence the innate immune response unlike Delta. Both Alpha and Delta have evolved to resist IFN treatment while they are still susceptible to RLR activation, further highlighting the importance of RLR-mediated, IFN-independent mechanisms in restricting SARS-CoV-2. Our studies reveal that SARS-CoV-2 Delta has integrated multiple mechanisms to silence host innate immune response and evade IFN response. Deltas silent replication and sustained suppression of host innate immune response, possibly resulting in delayed or reduced intervention by the adaptive immune response, could potentially contribute to the severe symptoms and poor recovery index associated with it.

immunology↗