Rab27a GTPase and its effector Myosin Va are host factors required for efficient Oropouche virus cell egress

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Concha, Juan O. ; Gutierrez, Kristel ; Barbosa, Natalia ; Rodrigues, Roger L. ; de Carvalho, Andreia N. ; Tavares, Lucas A. ; Rudd, Jared S. ; Costa, Cristina S. ; Andrade, Barbara Y. G. ; Espreafico, Enilza M. ; Crump, Colin M. ; daSilva, Luis L. P.

• Tipo de documento: Artigo Científico
• Fonte: PLOS PATHOGENS; v. 20, n. 8, p. 24-pg., 2024-08-01.

Resumo

Oropouche fever, a debilitating illness common in South America, is caused by Oropouche virus (OROV), an arbovirus. OROV belongs to the Peribunyaviridae family, a large group of RNA viruses. Little is known about the biology of Peribunyaviridae in host cells, especially assembly and egress processes. Our research reveals that the small GTPase Rab27a mediates intracellular transport of OROV induced compartments and viral release from infected cells. We show that Rab27a interacts with OROV glycoproteins and colocalizes with OROV during late phases of the infection cycle. Moreover, Rab27a activity is required for OROV trafficking to the cell periphery and efficient release of infectious particles. Consistently, depleting Rab27a's downstream effector, Myosin Va, or inhibiting actin polymerization also hinders OROV compartments targeting to the cell periphery and infectious viral particle egress. These data indicate that OROV hijacks Rab27a activity for intracellular transport and cell externalization. Understanding these crucial mechanisms of OROV's replication cycle may offer potential targets for therapeutic interventions and aid in controlling the spread of Oropouche fever. Since its identification in the early 1960s, Oropouche virus (OROV) has caused over 30 epidemics in Central and South America, infecting an estimated half a million people. Environmental changes, urbanization, and increased travel increase the risk of OROV spreading beyond its endemic regions. The lack of vaccines and specific antiviral treatments highlights the urgent need to better understand OROV biology. Previous research shows that OROV assembles in the Golgi complex of human cells, forming vesicular compartments that transport viral particles to the cell periphery, leading to virus spread. Our findings reveal that OROV hijacks the Rab27 GTPase and its effector, the motor protein Myosin Va, to facilitate viral egress. Specifically, we show that Rab27a associates with OROV glycoproteins and, along with Myosin Va, is found in viral-induced compartments at late infection stages. Depleting Rab27a or Myosin Va, or expressing defective Rab27a mutants, compromises the release of infectious viral particles. We propose that vesicles containing OROV exploit Rab27a/Myosin Va-mediated transport to competently reach the cell periphery and fuse with the plasma membrane, enabling their release and viral transmission to other cells. Understanding the molecular mechanisms underlying OROV replication will be crucial for developing future anti-OROV drugs, which are currently unavailable. (AU)

• Processo FAPESP: 19/26119-0 - Vírus emergentes e reemergentes: biologia, patogênese e prospecção
• Beneficiário: Eurico de Arruda Neto
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 19/02945-9 - Estudo dos mecanismos moleculares envolvidos na montagem do vírus oropouche
• Beneficiário: Natalia da Silva Barbosa
• Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Doutorado Direto
• Processo FAPESP: 23/02880-0 - Estudo das interações de SARS-CoV-2 com o sistema de endomembranas da célula hospedeira.
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• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 22/04533-2 - Estudo do tráfego do vírus Oropouche e sua relação com a modulação da via autofágica durante a infeção da célula hospedeira
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• Modalidade de apoio: Bolsas no Brasil - Mestrado
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• Processo FAPESP: 16/18356-4 - Estudo dos fatores celulares envolvidos na montagem e brotamento de Orthobunyavirus utilizando o vírus Oropouche como modelo
• Beneficiário: Natalia da Silva Barbosa
• Modalidade de apoio: Bolsas no Brasil - Doutorado Direto
• Processo FAPESP: 18/00297-7 - Estudo dos efeitos da proteína Nef do HIV-1 no sistema de endomembranas da célula hospedeira e suas implicações na patogênese viral
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• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 19/27725-1 - Estudo dos mecanismos pelos quais Nef do HIV-1 promove a infecciosidade viral neutralizando fatores de restrição da célula hospedeira
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• Modalidade de apoio: Bolsas no Brasil - Doutorado Direto
• Processo FAPESP: 19/02418-9 - Mecanismos moleculares envolvidos na montagem do Vírus Oropouche
• Beneficiário: Luis Lamberti Pinto da Silva
• Modalidade de apoio: Auxílio à Pesquisa - Regular