Accumulating RNA Hinders Antiviral Immunity and Promotes Neurodegeneration

Understanding how our immune system combats viral infections is a leading focus in immunology. Two groundbreaking studies by Chan et al. and Ru et al., published in the Journal of Experimental Medicine, reveal new insights into how the buildup of RNA due to defective RNA processing impairs antiviral immunity, particularly in the brain. Their work not only provides a detailed molecular mechanism but also sheds light on potential therapeutic targets for conditions such as SARS-CoV-2-induced brainstem encephalitis.

Why RNA Processing Is Critical for Immunity

The immune system relies on accurate communication at the molecular level. RNA—messenger molecules essential for protein synthesis—is tightly regulated to maintain cellular health. Defective removal of unnecessary RNA structures, like RNA lariats (looped RNA molecules formed during gene splicing), can disrupt this balance.

The studies focus on the enzyme DBR1 (RNA lariat debranching enzyme 1), responsible for breaking down RNA lariats post-splicing. Normally, DBR1 prevents RNA lariats from accumulating by hydrolyzing them into manageable forms, ready for degradation. However, inherited deficiencies of DBR1 impair this process, triggering a cascade of antiviral immune failures.

Chan et al. and Ru et al. independently uncovered the startling consequences of DBR1 deficiencies by studying individuals suffering from severe viral infections, including SARS-CoV-2-induced brainstem encephalitis. The findings highlight how RNA lariat buildup disrupts antiviral immunity through several mechanisms:

1. Reduced Stress Granule Formation

Stress granules (SGs) are critical for antiviral defense—they act as molecular command centers during viral infections. Ru et al. found that lariat accumulation interferes with the assembly of SGs by degrading G3BP1 and G3BP2 proteins, essential components of SGs.

2. Impaired PKR Activation

Protein kinase R (PKR), a key molecule in antiviral immunity, is activated by SGs. Without fully assembled SGs, PKR cannot efficiently stop viral replication. This makes cells more susceptible to viruses such as SARS-CoV-2, vesicular stomatitis virus, and herpes simplex virus (HSV-1).

3. Uncontrolled Viral Replication in the Brainstem

Chan et al. demonstrated that DBR1 mutations allow RNA lariats to pile up in brainstem neurons, disrupting intrinsic neuronal defenses. This environment creates a breeding ground for viruses, including SARS-CoV-2, leading to severe encephalitis—a hallmark of DBR1-associated immune defects.

Broader Implications of DBR1 Deficiency

DBR1’s role goes beyond regulating RNA lariats. The enzyme is implicated in diverse immune and disease mechanisms, such as controlling Toll-Like Receptor 3 (TLR3)-mediated central nervous system immunity or even modulating HIV-1 replication. These functions underscore the enzyme’s importance in both immune responses and neuroprotection. Interestingly, DBR1 deficiencies aren’t limited to immune dysfunction. They are also linked to rare neurological and developmental conditions, highlighting the interconnectedness of RNA metabolism with various physiological processes like nerve function and gene regulation.

Potential Therapeutic Insights

The work of Chan et al. suggests that restoring DBR1 function, either through gene therapy or targeted molecular interventions, could alleviate the immunodeficiencies caused by lariat RNA accumulation. Meanwhile, Ru et al. reveal that enhancing SG stability or PKR activation may provide alternate therapeutic approaches.

Broader Strategies Include:

• Nutriceuticals: Herbal compounds have been found to correct dysregulation of RNA modification, a hallmark of cancer progression (1). 
• Drug Targets: Develop compounds to stabilize G3BP proteins or directly activate PKR.
• Preventive Dietary Options: Reduce the amount of protein and food combinations. For example avoid eating animal protein and carbohydrates together in a meal. Also avoid eating sweets or high sugar fruit with any other carbs or protein. 

Understanding these pathways offers hope for combating not only viral encephalitis but also other RNA-processing-related disorders.

An Emerging Pattern: RNA-Binding Proteins in Neurodegenerative Disorders

Across various neurodegenerative disorders, a striking pattern emerges: proteins that bind to RNA are consistently found in tangled inclusions.

Abnormal Protein Inclusions

The incorrect enfolding of proteins inside cells is a shared trait among an ensemble of diseases, including Alzheimer's, Parkinson's, and Huntington's. Although the specific protein components of neuropathological inclusions vary across disorders, one class of proteins that is increasingly overrepresented is RNA-binding proteins. These proteins, including TDP-43, FUS, and TAF15, are found to be aberrantly aggregated. What's becoming clear is that proteins like tau and α-synuclein, often overlooked in the past, are actually capable of forming meaningful connections with RNA and other nucleic acids - connections that are anything but accidental.

Sources

4). Valeri, E., & Kajaste-Rudnitski, A. (2025). Antiviral immunity lassoed down by excess RNA. Journal of Experimental Medicine, 222(1).