ZFAND6 promotes TRAF2-dependent mitophagy to restrain cGAS-STING signaling

Kashif Shaikh; Melissa Bowman; Sarah M. McCormick; Linlin Gao; Jiawen Zhang; Jesse White; John Tawil; Arun Kapoor; Ravit Arav-Boger; Christopher C. Norbury; Edward W. Harhaj

doi:10.1016/j.isci.2024.111544

ZFAND6 promotes TRAF2-dependent mitophagy to restrain cGAS-STING signaling

Kashif Shaikh, Melissa Bowman, Sarah M. McCormick, Linlin Gao, Jiawen Zhang, Jesse White, John Tawil, Arun Kapoor, Ravit Arav-Boger, Christopher C. Norbury, Edward W. Harhaj

Research output: Contribution to journal › Article › peer-review

Abstract

ZFAND6 is a zinc finger protein that interacts with TNF receptor-associated factor 2 (TRAF2) and polyubiquitin chains and has been linked to tumor necrosis factor (TNF) signaling. Here, we report a previously undescribed function of ZFAND6 in maintaining mitochondrial homeostasis by promoting mitophagy. Deletion of ZFAND6 in bone marrow-derived macrophages (BMDMs) upregulates reactive oxygen species (ROS) and the accumulation of damaged mitochondria due to impaired mitophagy. Consequently, mitochondrial DNA (mtDNA) is released into the cytoplasm, triggering the spontaneous expression of interferon-stimulated genes (ISGs) in a stimulator of interferon genes (STING) dependent manner, which leads to enhanced viral resistance. Mechanistically, ZFAND6 bridges a TRAF2-cIAP1 interaction and mediates the recruitment of TRAF2 to damaged mitochondria, which is required for the initiation of ubiquitin-dependent mitophagy. Our results suggest that ZFAND6 promotes the interactions of TRAF2 and cIAP1 and the clearance of damaged mitochondria by mitophagy to maintain mitochondrial homeostasis.

Original language	English (US)
Article number	111544
Journal	iScience
Volume	28
Issue number	1
DOIs	https://doi.org/10.1016/j.isci.2024.111544
State	Published - Jan 17 2025

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@article{27392ec0f55b490386e512e41a802654,

title = "ZFAND6 promotes TRAF2-dependent mitophagy to restrain cGAS-STING signaling",

abstract = "ZFAND6 is a zinc finger protein that interacts with TNF receptor-associated factor 2 (TRAF2) and polyubiquitin chains and has been linked to tumor necrosis factor (TNF) signaling. Here, we report a previously undescribed function of ZFAND6 in maintaining mitochondrial homeostasis by promoting mitophagy. Deletion of ZFAND6 in bone marrow-derived macrophages (BMDMs) upregulates reactive oxygen species (ROS) and the accumulation of damaged mitochondria due to impaired mitophagy. Consequently, mitochondrial DNA (mtDNA) is released into the cytoplasm, triggering the spontaneous expression of interferon-stimulated genes (ISGs) in a stimulator of interferon genes (STING) dependent manner, which leads to enhanced viral resistance. Mechanistically, ZFAND6 bridges a TRAF2-cIAP1 interaction and mediates the recruitment of TRAF2 to damaged mitochondria, which is required for the initiation of ubiquitin-dependent mitophagy. Our results suggest that ZFAND6 promotes the interactions of TRAF2 and cIAP1 and the clearance of damaged mitochondria by mitophagy to maintain mitochondrial homeostasis.",

author = "Kashif Shaikh and Melissa Bowman and McCormick, {Sarah M.} and Linlin Gao and Jiawen Zhang and Jesse White and John Tawil and Arun Kapoor and Ravit Arav-Boger and Norbury, {Christopher C.} and Harhaj, {Edward W.}",

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year = "2025",

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doi = "10.1016/j.isci.2024.111544",

language = "English (US)",

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T1 - ZFAND6 promotes TRAF2-dependent mitophagy to restrain cGAS-STING signaling

AU - Shaikh, Kashif

AU - Bowman, Melissa

AU - McCormick, Sarah M.

AU - Gao, Linlin

AU - Zhang, Jiawen

AU - White, Jesse

AU - Tawil, John

AU - Kapoor, Arun

AU - Arav-Boger, Ravit

AU - Norbury, Christopher C.

AU - Harhaj, Edward W.

PY - 2025/1/17

Y1 - 2025/1/17

N2 - ZFAND6 is a zinc finger protein that interacts with TNF receptor-associated factor 2 (TRAF2) and polyubiquitin chains and has been linked to tumor necrosis factor (TNF) signaling. Here, we report a previously undescribed function of ZFAND6 in maintaining mitochondrial homeostasis by promoting mitophagy. Deletion of ZFAND6 in bone marrow-derived macrophages (BMDMs) upregulates reactive oxygen species (ROS) and the accumulation of damaged mitochondria due to impaired mitophagy. Consequently, mitochondrial DNA (mtDNA) is released into the cytoplasm, triggering the spontaneous expression of interferon-stimulated genes (ISGs) in a stimulator of interferon genes (STING) dependent manner, which leads to enhanced viral resistance. Mechanistically, ZFAND6 bridges a TRAF2-cIAP1 interaction and mediates the recruitment of TRAF2 to damaged mitochondria, which is required for the initiation of ubiquitin-dependent mitophagy. Our results suggest that ZFAND6 promotes the interactions of TRAF2 and cIAP1 and the clearance of damaged mitochondria by mitophagy to maintain mitochondrial homeostasis.

AB - ZFAND6 is a zinc finger protein that interacts with TNF receptor-associated factor 2 (TRAF2) and polyubiquitin chains and has been linked to tumor necrosis factor (TNF) signaling. Here, we report a previously undescribed function of ZFAND6 in maintaining mitochondrial homeostasis by promoting mitophagy. Deletion of ZFAND6 in bone marrow-derived macrophages (BMDMs) upregulates reactive oxygen species (ROS) and the accumulation of damaged mitochondria due to impaired mitophagy. Consequently, mitochondrial DNA (mtDNA) is released into the cytoplasm, triggering the spontaneous expression of interferon-stimulated genes (ISGs) in a stimulator of interferon genes (STING) dependent manner, which leads to enhanced viral resistance. Mechanistically, ZFAND6 bridges a TRAF2-cIAP1 interaction and mediates the recruitment of TRAF2 to damaged mitochondria, which is required for the initiation of ubiquitin-dependent mitophagy. Our results suggest that ZFAND6 promotes the interactions of TRAF2 and cIAP1 and the clearance of damaged mitochondria by mitophagy to maintain mitochondrial homeostasis.

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ZFAND6 promotes TRAF2-dependent mitophagy to restrain cGAS-STING signaling

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