Influenza A virus protein PB1-F2 impairs innate immunity by inducing mitophagy

[tetano]

Autophagy. 2020 Feb 3. doi: 10.1080/15548627.2020.1725375. [Epub ahead of print] Influenza A virus protein PB1-F2 impairs innate immunity by inducing mitophagy.

Wang R^1,2, Zhu Y^1,2, Ren C^1,2, Yang S^1,2, Tian S^1,2, Chen H^1,2, Jin M^1,2, Zhou H^1,2.
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Abstract

Influenza A virus (IAV) infection induces mitophagy, which is essential for the clearance of damaged mitochondria. Dysfunctional mitochondria can be selectively targeted by PINK1, which recruits PRKN/PARK2 and leads to subsequent mitochondrial sequestration within autophagosomes. The IAV PB1-F2 protein translocates to mitochondria, accelerates the mitochondrial fragmentation and impairs the innate immunity. However, whether PB1-F2 mediates IAV-induced mitophagy and the relation between mitophagy and PB1-F2-attenuated innate immunity remain obscure. Here, we showed that PB1-F2 translocated to mitochondria by interacting and colocalizing with TUFM (Tu translation elongation factor, mitochondrial). Further studies revealed that PB1-F2 induced complete mitophagy, which required the interactions of PB1-F2 with both TUFM and MAP1LC3B/LC3B that mediated the autophagosome formation. PB1-F2-induced mitophagy was critical for the MAVS (mitochondrial antiviral signaling protein) degradation and led to its suppression of the type I IFN production. Importantly, the C-terminal LIR motif of PB1-F2 protein was demonstrated to be essential for its mitophagy induction and attenuated innate immunity. In conclusion, PB1-F2-induced mitophagy strongly correlates with impaired cellular innate immunity, revealing it is a potential therapeutic target.


KEYWORDS:

LC3B; MAVS; TUFM; influenza PB1-F2 protein; innate immunity; mitophagy

PMID: 32013669 DOI: 10.1080/15548627.2020.1725375