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TMEM106B es un receptor que media la entrada en las células del SARS-CoV-2 independientemente de la ACE2

Jim Baggen¹, Maarten Jacquemyn¹, Leentje Persoons¹

¹KU Leuven Department of Microbiology, Immunology and Transplantation, Laboratory of Virology and Chemotherapy, Rega Institute, Leuven 3000, Belgium.

|July 8, 2023

Resumen

Los investigadores descubrieron que TMEM106B actúa como un receptor alternativo para la entrada del SARS-CoV-2 en las células que carecen de ACE2. Este hallazgo revela un nuevo mecanismo para la infección por SARS-CoV-2 y posibles objetivos terapéuticos.

Área de la Ciencia:

Virología
Biología celular
Biología estructural

Sus antecedentes:

El SARS-CoV-2 exhibe un tropismo de tejido amplio, influenciado por la disponibilidad del receptor de entrada de la célula huésped.
La enzima convertidora de angiotensina 2 (ACE2) es el principal receptor conocido para la entrada de SARS-CoV-2.
Comprender las vías de entrada alternativas es crucial para combatir la propagación del virus.

Objetivo del estudio:

Para identificar receptores celulares alternativos para la entrada del SARS-CoV-2 más allá de ACE2.
Para aclarar el mecanismo de la interacción del SARS-CoV-2 con el TMEM106B.
Investigar el papel de TMEM106B en la fusión viral y la infección.

Principales métodos:

Se utilizó la cristalografía de rayos X y la microscopía electrónica criogénica (cryo-EM) para determinar las interacciones estructurales.
Se utilizó la espectrometría de masas de intercambio de hidrógeno y deuterio (HDX-MS) para analizar la dinámica de las proteínas.
Se probó la eficacia de los anticuerpos monoclonales específicos de TMEM106B en el bloqueo de la infección viral.

Principales resultados:

Se identificó TMEM106B, una proteína de transmembrana lisosómica, como un receptor de entrada alternativo del SARS-CoV-2 en las células ACE2-negativas.
Se ha demostrado que una mutación específica de Spike (E484D) mejora la unión a TMEM106B y la entrada viral.
Se demostró que los anticuerpos específicos de TMEM106B inhiben la infección por SARS-CoV-2.
El análisis estructural reveló que el dominio luminal TMEM106B interactúa con el motivo de unión al receptor Spike del SARS-CoV-2.
Se observó que TMEM106B promueve la formación de síncito mediado por picos, lo que indica un papel en la fusión viral.

Conclusiones:

TMEM106B media la entrada del SARS-CoV-2 independientemente del ACE2.
Las interacciones cooperativas entre el sulfato de heparán y TMEM106B facilitan la infección por SARS-CoV-2.
TMEM106B representa un nuevo objetivo para las estrategias antivirales contra el SARS-CoV-2.

Palabras clave:

Entrada independiente del ACE2 En el caso del SARS-CoV-2 En el caso de los vehículos con ruedas de seguridad:Estructura cristalina del TMEM106B Neutralización de anticuerpos el coronavirus Crio-EM receptor de entrada

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