# TfR1 facilitates influenza virus endocytosis and uncoating by interacting with NA and M1 via extracellular and intracellular domains

## TL;DR

This study reveals how the transferrin receptor 1 (TfR1) helps influenza viruses enter and uncoat in human cells, offering new insights for antiviral therapies.

## Contribution

The study identifies TfR1 as a dual-function host protein that interacts with both NA and M1 proteins of influenza virus during entry and uncoating.

## Key findings

- TfR1 binds to viral neuraminidase (NA) via its extracellular domain to initiate endocytosis.
- TfR1 degrades viral matrix protein 1 (M1) via its intracellular domain to promote nucleocapsid uncoating.
- TfR1's role in viral degradation is also observed in measles and rabies viruses, suggesting a broader antiviral strategy.

## Abstract

An intriguing enigma in virology is the utilization of transferrin receptor 1 (TfR1) by various viruses as an entry portal into host cells, a mechanism that remains relatively underexplored. In this study, we report a strategy to investigate the multifaceted aspects of viral entry, using Influenza A viruses (IAVs) as a model system. By decorating the sialylated viral envelope with photo-crosslinking moieties, we identify and elucidate the pivotal role of TfR1 in this process. Our results demonstrate that TfR1 initially functions as a receptor, interacting with the viral neuraminidase (NA) through its extracellular apical domain, thereby initiating viral endocytosis. Subsequently, TfR1 acts as a matrix degradator, engaging its intracellular stop-transfer sequence with the viral matrix protein 1 (M1), which in turn triggers proteasome- and aggresome-mediated nucleocapsid uncoating. The identification of the molecular interactions between TfR1 and NA, as well as the reciprocal degradation of TfR1 and M1 not only illuminates a cellular pathway that enriches our understanding of viral entry mechanisms but also presents exciting avenues for the development of innovative antiviral strategies beyond IAVs.

Influenza viruses are masters of exploiting human cells, but how they hijack cellular machinery to enter and infect hosts remains partially understood. In this study, we combined cutting-edge metabolic glycan labeling and photo-crosslinking technologies to uncover a dual role of the iron transporter transferrin receptor 1 (TfR1) in influenza A virus (IAV) infection. Using innovative chemical tools to tag viral surface sugars, we discovered that TfR1 acts as a “gateway” for the virus: first, it binds to the viral neuraminidase (NA) protein to trigger entry into cells via extracellular domains, and later, it degrades virus structural matrix protein (M1) via intracellular domains. This two-step mechanism bridges critical gaps in our understanding of how viruses enter cells and uncoat their genetic material. Importantly, TfR1’s ability to degrade viral proteins extends to other pathogens like measles and rabies viruses, suggesting a universal strategy for antiviral therapies. By revealing how a single host protein facilitates both viral invasion and self-destruction, our work opens new avenues for designing drugs that disrupt these interactions, potentially offering broad protection against multiple deadly viruses. This discovery not only deepens our knowledge of viral infections but also highlights TfR1 as a promising target for next-generation antiviral treatments.