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Updated: May 3, 2026
A High Resolution Method to Monitor Phosphorylation-dependent Activation of IRF3
Published on: January 24, 2016
Identification of an endocytic signal essential for the antiviral action of IFITM3
Rui Jia1, Fengwen Xu, Jin Qian
1Key Laboratory of Molecular Microbiology and Biotechnology (Ministry of Education) and Key Laboratory of Microbial Functional Genomics (Tianjin), College of Life Sciences, Nankai University, Tianjin, 300071, China.
Abstract:
Members of the interferon-induced transmembrane (IFITM) protein family inhibit the entry of a wide range of viruses. Viruses often exploit the endocytosis pathways to invade host cells and escape from the endocytic vesicles often in response to low pH. Localization to these endocytic vesicles is essential for IFITM3 to interfere with the cytosolic entry of pH-dependent viruses. However, the nature of the sorting signal that targets IFITM3 to these vesicles is poorly defined. In this study, we report that IFITM3 possesses a YxxΦ sorting motif, i.e. 20-YEML-23, that enables IFITM3 to undergo endocytosis through binding to the μ2 subunit of the AP-2 complex. IFITM3 accumulates at the plasma membrane as a result of either mutating 20-YEML-23, depleting the μ2 subunit or overexpressing μ2 mutants. Importantly, blocking endocytosis of IFITM3 abrogates its ability to inhibit pH-dependent viruses. We have therefore identified a critical sorting signal, namely 20-YEML-23, that controls both the endocytic trafficking and the antiviral action of IFITM3. This finding also reveals that as an endocytic protein, IFITM3 first arrives at the plasma membrane before it is endocytosed and further traffics to the late endosomes where it acts to impede virus entry.
Insights
Interferon-induced transmembrane protein 3 (IFITM3) uses a YEML sorting signal for endocytosis, crucial for its antiviral activity against pH-dependent viruses. This motif targets IFITM3 to endocytic vesicles, where it blocks viral entry.
Area of Science:
- Virology
- Cell Biology
- Immunology
Background:
- Interferon-induced transmembrane (IFITM) proteins are key antiviral factors.
- Viruses utilize endocytosis for host cell entry, often escaping endosomes at low pH.
- IFITM3's antiviral function relies on its localization to endocytic vesicles.
Purpose of the Study:
- To identify the sorting signal responsible for IFITM3's endocytic trafficking.
- To understand how this signal influences IFITM3's antiviral activity.
Main Methods:
- Mutational analysis of the YxxΦ motif (20-YEML-23) in IFITM3.
- Investigating IFITM3 interaction with the AP-2 complex's μ2 subunit.
- Assessing the impact of endocytosis inhibition on IFITM3's antiviral efficacy.
Main Results:
- IFITM3 contains a YEML sorting motif (20-YEML-23) that mediates endocytosis via μ2-adaptin binding.
- Mutating this motif or disrupting μ2 interaction leads to IFITM3 accumulation at the plasma membrane.
- Blocking IFITM3 endocytosis significantly reduces its ability to inhibit pH-dependent viruses.
Conclusions:
- The 20-YEML-23 motif is a critical sorting signal for IFITM3 endocytosis and antiviral action.
- IFITM3's antiviral mechanism involves its trafficking to late endosomes after initial plasma membrane arrival and endocytosis.
- This study elucidates the molecular basis for IFITM3's localization and its role in cellular defense against viral infections.
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