Coxsackievirus B3–Mediated INTS10 Cleavage: A Strategic Mechanism Driving Viral Replication #TopTeachers

 

Coxsackievirus B3 (CVB3) is a positive-sense single-stranded RNA virus belonging to the genus Enterovirus in the Picornaviridae family. It is widely recognized for causing viral myocarditis, pancreatitis, and other inflammatory diseases in humans. Like many RNA viruses, CVB3 has evolved sophisticated mechanisms to hijack host cellular machinery and create a favorable environment for its replication. One emerging area of research focuses on how CVB3 manipulates host nuclear proteins, particularly INTS10, to promote viral propagation. The cleavage of INTS10 by CVB3 represents a strategic viral adaptation that disrupts host RNA processing and enhances viral replication efficiency.

INTS10 is a key subunit of the Integrator complex, a multiprotein assembly associated with RNA polymerase II. The Integrator complex plays a crucial role in the 3′-end processing of small nuclear RNAs (snRNAs) and regulates transcription of various genes. By maintaining proper RNA maturation and transcriptional control, INTS10 contributes to normal cellular homeostasis. Disruption of INTS10 function can therefore have broad consequences on gene expression, RNA stability, and cellular defense mechanisms.

During infection, CVB3 produces viral proteases—primarily 2A and 3C proteases—that cleave specific host proteins to redirect cellular resources toward viral replication. INTS10 has been identified as one such target. The cleavage of INTS10 results in the generation of truncated fragments that are unable to perform their normal biological functions within the Integrator complex. This proteolytic event effectively dismantles part of the host’s RNA processing machinery, impairing normal transcriptional regulation.

The functional consequence of INTS10 cleavage is multifaceted. First, disruption of the Integrator complex leads to reduced processing of snRNAs, which are essential components of the spliceosome. This impairs pre-mRNA splicing and broadly affects host gene expression. Second, altered transcriptional regulation can suppress the expression of antiviral genes, including interferon-stimulated genes that are critical for innate immune defense. By dampening these antiviral responses, CVB3 creates a more permissive intracellular environment for viral genome replication and protein synthesis.

Additionally, host RNA synthesis competes with viral RNA replication for nucleotides, ribosomes, and other essential factors. By interfering with host transcription and RNA maturation through INTS10 cleavage, CVB3 shifts the balance of cellular resources toward viral RNA production. This strategic redirection enhances the efficiency of viral genome amplification and accelerates the production of progeny virions. Consequently, viral spread within tissues is amplified, contributing to disease severity.

Another important dimension of INTS10 cleavage involves its potential impact on cellular stress pathways and apoptosis. Viral infections often trigger programmed cell death as a defense mechanism to limit viral dissemination. However, viruses like CVB3 modulate apoptotic pathways to optimize replication timing. Disruption of transcriptional regulators such as INTS10 may influence stress-response signaling and delay apoptosis, providing additional time for viral assembly and release before cell lysis occurs.

From a broader virological perspective, the targeting of nuclear transcription-associated proteins by cytoplasmic RNA viruses underscores the complexity of host–virus interactions. Although CVB3 replicates in the cytoplasm, it exerts significant influence over nuclear processes. This highlights how viruses extend their regulatory reach beyond their primary replication sites to comprehensively remodel host cellular architecture. The cleavage of INTS10 is therefore not an isolated event but part of a coordinated viral strategy to suppress host defenses while maximizing replication efficiency.

Understanding the molecular mechanisms behind CVB3-mediated INTS10 cleavage has important therapeutic implications. If specific viral proteases are responsible for this cleavage event, targeted protease inhibitors could potentially preserve Integrator complex function and maintain antiviral gene expression. Furthermore, stabilizing INTS10 or preventing its cleavage may represent a novel host-directed therapeutic strategy to limit viral replication without directly targeting viral RNA, thereby reducing the likelihood of resistance development.

In conclusion, CVB3-mediated cleavage of INTS10 exemplifies a highly strategic viral mechanism that disrupts host RNA processing, suppresses antiviral responses, and reallocates cellular resources to favor viral replication. By dismantling key components of the transcriptional machinery, CVB3 enhances its propagation and pathogenic potential. Continued research into this interaction will deepen our understanding of viral pathogenesis and may pave the way for innovative antiviral therapies targeting host–virus molecular interfaces.

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