Abstract
Human Respiratory Syncytial Virus (HRSV) is a leading cause of bronchopneumonia in infants and the elderly. To date, knowledge of viral and host protein interactions within HRSV is limited and are critical areas of research. Here, we show that HRSV Matrix (M) protein interacts with the cellular adaptor protein complex 3 specifically via its medium subunit (AP-3Mu3A). This novel protein-protein interaction was first detected via yeast-two hybrid screen and was further confirmed in a mammalian system by immunofluorescence colocalization and co-immunoprecipitation. This novel interaction is further substantiated by the presence of a known tyrosine-based adaptor protein MU subunit sorting signal sequence, YXXФ: where Ф is a bulky hydrophobic residue, which is conserved across the related RSV M proteins. Analysis of point-mutated HRSV M derivatives indicated that AP-3Mu3A- mediated trafficking is contingent on the presence of the tyrosine residue within the YXXL sorting sequence at amino acids 197–200 of the M protein. AP-3Mu3A is up regulated at 24 hours post-infection in infected cells versus mock-infected HEp2 cells. Together, our data suggests that the AP-3 complex plays a critical role in the trafficking of HRSV proteins specifically matrix in epithelial cells. The results of this study add new insights and targets that may lead to the development of potential antivirals and attenuating mutations suitable for candidate vaccines in the future.
Highlights
Human Respiratory Syncytial Virus (HRSV) is the leading cause of acute lower respiratory tract infection (ALRI) in infants and it is estimated that globally 66,000–199,000 children younger than 5 years died from HRSV-associated ALRI in 2005 [1]
The HRSV produces its own matrix proteins and competes with the transfected mutant M protein and the reduction of viral titer may be due to mutant M protein incorporation into viral assembly and budding
The virus stuck on the cell membrane may not have been released into the media supernatant and this may account for reduction of viral titers in the mutant cell group
Summary
Human Respiratory Syncytial Virus (HRSV) is the leading cause of acute lower respiratory tract infection (ALRI) in infants and it is estimated that globally 66,000–199,000 children younger than 5 years died from HRSV-associated ALRI in 2005 [1]. HRSV belongs to the Paramyxoviridae family and is an enveloped, negative sense, single-stranded RNA virus encoding 11 proteins [2]. HRSV infection occurs preferentially through the apical surface of the most superficial layer of the polarized epithelium of the respiratory tract [3, 4]. Human Respiratory Syncytial Virus matrix protein interacts with cellular adaptor protein complex 3
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