Influenza A virus propagation requires the activation of the unfolded protein response and the accumulation of insoluble protein aggregates
Mariana Marques,
Bruno Ramos,
Hélio Albuquerque,
Marisa Pereira,
Diana Roberta Ribeiro,
Alexandre Nunes,
Jéssica Sarabando,
Daniela Brás,
Ana Rita Ferreira,
Rui Vitorino,
Maria João Amorim,
Artur M.S. Silva,
Ana Raquel Soares,
Daniela Ribeiro
Affiliations
Mariana Marques
Institute of Biomedicine – iBiMED, Department of Medical Sciences University of Aveiro, Aveiro, Portugal
Bruno Ramos
Institute of Biomedicine – iBiMED, Department of Medical Sciences University of Aveiro, Aveiro, Portugal
Hélio Albuquerque
LAQV-REQUIMTE, Department of Chemistry, University of Aveiro, Campus de Santiago, 3810-193 Aveiro, Portugal
Marisa Pereira
Institute of Biomedicine – iBiMED, Department of Medical Sciences University of Aveiro, Aveiro, Portugal
Diana Roberta Ribeiro
Institute of Biomedicine – iBiMED, Department of Medical Sciences University of Aveiro, Aveiro, Portugal
Alexandre Nunes
Institute of Biomedicine – iBiMED, Department of Medical Sciences University of Aveiro, Aveiro, Portugal
Jéssica Sarabando
Institute of Biomedicine – iBiMED, Department of Medical Sciences University of Aveiro, Aveiro, Portugal
Daniela Brás
Instituto Gulbenkian de Ciência, 2780-156 Oeiras, Portugal
Ana Rita Ferreira
Institute of Biomedicine – iBiMED, Department of Medical Sciences University of Aveiro, Aveiro, Portugal
Rui Vitorino
Institute of Biomedicine – iBiMED, Department of Medical Sciences University of Aveiro, Aveiro, Portugal
Maria João Amorim
Instituto Gulbenkian de Ciência, 2780-156 Oeiras, Portugal; Católica Biomedical Research Centre, Católica Medical School, Universidade Católica Portuguesa, 1649-023 Lisboa, Portugal
Artur M.S. Silva
LAQV-REQUIMTE, Department of Chemistry, University of Aveiro, Campus de Santiago, 3810-193 Aveiro, Portugal
Ana Raquel Soares
Institute of Biomedicine – iBiMED, Department of Medical Sciences University of Aveiro, Aveiro, Portugal
Daniela Ribeiro
Institute of Biomedicine – iBiMED, Department of Medical Sciences University of Aveiro, Aveiro, Portugal; Corresponding author
Summary: Influenza A virus (IAV) employs multiple strategies to manipulate cellular mechanisms and support proper virion formation and propagation. In this study, we performed a detailed analysis of the interplay between IAV and the host cells’ proteostasis throughout the entire infectious cycle. We reveal that IAV infection activates the inositol requiring enzyme 1 (IRE1) branch of the unfolded protein response, and that this activation is important for an efficient infection. We further observed the accumulation of virus-induced insoluble protein aggregates, containing both viral and host proteins, associated with a dysregulation of the host cell RNA metabolism. Our data indicate that this accumulation is important for IAV propagation and favors the final steps of the infection cycle, more specifically the virion assembly. These findings reveal additional mechanisms by which IAV disrupts host proteostasis and uncovers new cellular targets that can be explored for the development of host-directed antiviral strategies.
