MLKL‒OPTN axis regulates herpesvirus‐induced neurological sequelae

TL;DR

This study reveals how the MLKL and OPTN proteins interact to control HSV-1 infection and prevent neurological damage similar to multiple sclerosis.

Contribution

The study identifies a new regulatory axis between MLKL and OPTN that governs HSV-1 pathogenesis and neurological outcomes.

Findings

MLKL regulates HSV-1 transport to the nucleus and forms p-MLKL bodies that cause oligodendrocyte death and demyelination.

OPTN negatively modulates MLKL to restrict HSV-1 infection and prevent oligodendrocyte death.

Pharmacological inhibition of MLKL with NSA reduces neurological deficits and preserves myelin in HSV-1 models.

Abstract

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.

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.

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.

MLKL plays a significant role in regulating endosomal transport of HSV‐1 to nucleus during early stages of infection.Formation of p‐MLKL bodies during HSV‐1 infection leads to death of oligodendrocyte and subsequent demyelination.OPTN can negatively modulate MLKL levels to restrict infection and consequential oligodendrocyte death during HSV‐1 infection.

MLKL plays a significant role in regulating endosomal transport of HSV‐1 to nucleus during early stages of infection.

Formation of p‐MLKL bodies during HSV‐1 infection leads to death of oligodendrocyte and subsequent demyelination.

OPTN can negatively modulate MLKL levels to restrict infection and consequential oligodendrocyte death during HSV‐1 infection.

MLKL plays a significant role in regulating endosomal transport of HSV‐1 to nucleus during early stages of infection.Formation of p‐MLKL bodies during HSV‐1 infection leads to death of oligodendrocyte and subsequent demyelination.OPTN can negatively modulate MLKL levels to restrict infection and consequential oligodendrocyte death during HSV‐1 infection.

MLKL plays a significant role in regulating endosomal transport of HSV‐1 to nucleus during early stages of infection.

Formation of p‐MLKL bodies during HSV‐1 infection leads to death of oligodendrocyte and subsequent demyelination.

OPTN can negatively modulate MLKL levels to restrict infection and consequential oligodendrocyte death during HSV‐1 infection.

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