MLKL‒OPTN axis regulates herpesvirus-induced neurological sequelae

Abstract

Background: Herpes simplex virus-1 (HSV-1) infections are lifelong and linked to neurological diseases such as multiple sclerosis (MS), yet the underlying mechanisms in the host remain poorly understood.

Methods and Results: This study investigates new molecular dynamics following HSV-1 infection, uncovering the pivotal role of the mixed lineage kinase domain-like (MLKL) protein. Beyond its known function in necroptosis, MLKL was found to control HSV-1 transport into the nucleus, tightly regulated by Optineurin (OPTN). We evidenced an essential regulatory interaction between MLKL and OPTN, governing MLKL's activity in both necroptosis-dependent and independent pathways. In vivo, studies using Optn knockout mice demonstrated how this MLKL-OPTN axis contributes to demyelination and neurological symptoms mimicking MS. This axis critically prevents oligodendrocyte death and the associated demyelination during HSV-1 infection. Furthermore, pharmacological interventions with Necrosulfonamide (NSA), an MLKL inhibitor, showed therapeutic potential in preserving myelin integrity and reducing neurological deficits in HSV-1-infected models, suggesting a viable strategy for managing virus-induced neurodegeneration.

Conclusion: Our findings highlight the significant role of MLKL in HSV-1 pathogenesis and suggest that MLKL dysregulation is a key mechanism behind severe neurological damage.

Keywords

cell death / demyelinating disorders / HSV-1 / MLKL / OPTN

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2025 The Author(s). Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.