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Mitophagy and Innate Immunity in Infection.

ABSTRACT: Mitochondria have several quality control mechanisms by which they maintain cellular homeostasis and ensure that the molecular machinery is protected from stress. Mitophagy, selective autophagy of mitochondria, promotes mitochondrial quality control by inducing clearance of damaged mitochondria via the autophagic machinery. Accumulating evidence suggests that mitophagy is modulated by various microbial components in an attempt to affect the innate immune response to infection. In addition, mitophagy plays a key role in the regulation of inflammatory signaling, and mitochondrial danger signals such as mitochondrial DNA translocated into the cytosol can lead to exaggerated inflammatory responses. In this review, we present current knowledge on the functional aspects of mitophagy and its crosstalk with innate immune signaling during infection. A deeper understanding of the role of mitophagy could facilitate the development of more effective therapeutic strategies against various infections.

SUBMITTER: Cho DH

PROVIDER: S-EPMC6999710 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Mitophagy and Innate Immunity in Infection.

Cho Dong-Hyung DH Kim Jin Kyung JK Jo Eun-Kyeong EK

Molecules and cells 20200101 1

Mitochondria have several quality control mechanisms by which they maintain cellular homeostasis and ensure that the molecular machinery is protected from stress. Mitophagy, selective autophagy of mitochondria, promotes mitochondrial quality control by inducing clearance of damaged mitochondria via the autophagic machinery. Accumulating evidence suggests that mitophagy is modulated by various microbial components in an attempt to affect the innate immune response to infection. In addition, mitop ...[more]

PMID: 31999918

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Project description: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.Abbreviations: BCL2L13: BCL2 like 13; BECN1: beclin 1; BNIP3L/Nix: BCL2 interacting protein 3 like; CQ: chloroquine; DDX58: DExD/H-box helicase 58; eGFP: enhanced green fluorescent protein; hpi: hours post infection; IAV: influenza A virus; IFN: interferon; IP: immunoprecipitation; LIR: LC3-interacting region; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MAVS: mitochondrial antiviral signaling protein; MMP: mitochondrial membrane potential; MOI, multiplicity of infection; mRFP: monomeric red fluorescent protein; NBR1: NBR1 autophagy cargo receptor; NC: negative control; NLRP3: NLR family pyrin domain containing 3; PINK1: PTEN induced kinase 1; PRKN/PARK2: parkin RBR E3 ubiquitin protein ligase; RLR: RIG-I-like-receptor; ROS: reactive oxygen species; SEV: sendai virus; SQSTM1/p62: sequestosome 1; TAX1BP1: Tax1 binding protein 1; TM: transmembrane; TOMM20/40: translocase of outer mitochondrial membrane 20/40; TUFM: Tu translation elongation factor, mitochondrial.

Dataset Information

Mitophagy and Innate Immunity in Infection.

Publications

Mitophagy and Innate Immunity in Infection.

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