# Host cellular protein RAB33B facilitates influenza viral replication and modulates M2 trafficking by enhancing autophagy

## TL;DR

This study reveals how the influenza virus uses a host protein called RAB33B to boost its replication by manipulating autophagy and M2 protein trafficking.

## Contribution

The study identifies RAB33B as a novel host factor that facilitates influenza viral replication through autophagy and M2 trafficking.

## Key findings

- RAB33B is up-regulated by IAV M2 and promotes viral replication by enhancing autophagy.
- Autophagy facilitates M2 membrane trafficking via autophagic-like vesicles involving RAB33B and LC3.
- ATG16L1 and TBC1D25 modulate RAB33B activity to influence IAV M2-induced autophagy and replication.

## Abstract

Influenza A virus (IAV) remains a major global health threat. Its M2 protein plays crucial roles in viral fusion, transportation, assembly, and release. Recent studies have shown that IAV impairs host autophagy flux to enhance viral replication. However, the precise mechanisms by which IAV M2 manipulates host cellular autophagy during virus replication remain unclear. In this study, we analysed cellular transcriptional responses of cells to IAV M2 overexpression and identified RAB GTPase protein RAB33B as a key factor. RAB33B was significantly up-regulated by IAV M2 and promoted IAV replication by enhancing autophagy. We further found that autophagy regulates the interaction of IAV M2, RAB33B, and LC3, facilitating M2 membrane trafficking through autophagic-like vesicles. In addition, ATG16L1 (an effector of RAB33B) and TBC1D25 (a GTPase-activating protein for RAB33B) contributed to IAV M2-induced autophagy, thereby affecting viral replication. Collectively, our findings reveal a novel mechanism in which RAB33B is essential for IAV M2 trafficking to the plasma membrane, facilitating viral replication through enhanced autophagy. These insights shed new light on the autophagy-based cellular transport mechanisms of IAV M2 and highlight potential antiviral targets.

The online version contains supplementary material available at 10.1186/s13567-025-01560-6.