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Coxsackievirus B3 targets TFEB to disrupt lysosomal function
Yasir Mohamud1,2, Hui Tang1,3, Yuan Chao Xue1,2
1Centre for Heart Lung Innovation, St. Paul's Hospital, Vancouver, Canada.
Autophagy
|March 11, 2021
Summary
Coxsackievirus B3 (CVB3) disrupts autophagy by cleaving transcription factor EB (TFEB), a key regulator. This viral proteinase 3C action impairs TFEB function, enhancing viral infection and disease.
Area of Science:
- Virology
- Molecular Biology
- Cellular Biology
Background:
- Coxsackievirus B3 (CVB3) causes viral myocarditis and neurological disorders.
- CVB3 utilizes host autophagy for viral replication, with viral proteinases disrupting this process.
- Mechanisms of viral proteinase-mediated autophagy disruption are not fully understood.
Purpose of the Study:
- To identify novel targets of CVB3 proteinase 3C within the autophagy pathway.
- To elucidate the role of transcription factor EB (TFEB) in CVB3 pathogenesis.
- To investigate how CVB3 infection impacts TFEB function and localization.
Main Methods:
- Time-course CVB3 infections in cellular models.
- Western blotting to detect TFEB cleavage and fragment formation.
- In vitro cleavage assays using purified CVB3 proteinase 3C and TFEB.
- Site-directed mutagenesis to identify the TFEB cleavage site.
- Reporter assays to assess TFEB transcriptional activity.
- Immunofluorescence microscopy to analyze TFEB localization.
- Viral egress assays.
Main Results:
- CVB3 proteinase 3C directly cleaves TFEB, generating a ~63 kDa fragment.
- Cleavage occurs after glutamine 60, resulting in a loss of TFEB transcriptional function.
- CVB3 infection also induces cleavage-independent TFEB nuclear translocation via calcineurin.
- Both full-length TFEB and the TFEB cleavage fragment (TFEB [Δ60]) contribute to viral egress.
Conclusions:
- CVB3 targets TFEB for proteolytic processing by proteinase 3C to dysregulate host lysosomal function.
- Cleavage of TFEB impairs its transcriptional activity, promoting viral infection.
- TFEB plays a dual role in viral egress, both in its full-length and cleaved forms.
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