Sunday, May 18, 2025
5/18/2025
ZFAND6 regulation of mitophagy and inflammation - Pattern recognition receptors (PRRs), including the DNA sensing nucleotidyl transferase cGAS and the endoplasmic reticulum (ER)-localized adaptor STING, detect pathogen-associated molecular patterns (PAMPs), which in turn leads to induction of type I interferons (IFNs) via IRF3 and NF-κB transcription factors. The cGAS- STING DNA sensing pathway can also be aberrantly activated by damage-associated molecular patterns (DAMPs) such as mitochondrial DNA (mtDNA). To maintain mitochondrial quality control and homeostasis, cells have evolved dedicated mechanisms to remove damaged or superfluous mitochondria through mitophagy, an autophagy-mediated lysosomal degradation pathway. Impaired mitophagy leads to the release of mtDNA into the cytoplasm, triggering activation of the cGAS-STING pathway and induction of type I IFN and inflammatory cytokines. Emerging studies have implicated aberrant activation of the cGAS-STING pathway in numerous inflammatory diseases including aging-related chronic inflammation and neurodegeneration. However, the cellular mechanisms that prevent the release of mtDNA into the cytoplasm and subsequent cGAS-STING activation and chronic inflammation are incompletely understood. Our preliminary data indicate that the zinc finger protein and A20 family member ZFAND6 functions as a novel regulator of mitophagy. We have generated Zfand6–/– mice and found that Zfand6–/– bone marrow-derived macrophages (BMDMs) exhibited spontaneous expression of interferon-stimulated genes (ISGs) in a STING-dependent manner. The ISGs were upregulated in Zfand6–/– cells due to the accumulation of damaged mitochondria accompanied by increased reactive oxygen species (ROS) and decreased mitochondrial membrane potential. Zfand6–/– cells exhibited impaired mitophagy basally and after acute mitochondrial damage. ZFAND6 interacts with the E3 ubiquitin ligase TRAF2 and promotes its recruitment to damaged mitochondria suggesting that ZFAND6 may be an adaptor or shuttling protein for TRAF2. Zfand6–/– mice spontaneously accumulate lymphoid aggregates in their lungs and are highly sensitive to inflammatory stimuli, likely through mitochondrial DAMPs priming innate immune sensing pathways such as cGAS-STING and the NLRP3 inflammasome. The central hypothesis driving these investigations is that ZFAND6 serves as an adaptor for TRAF2 that is essential for TRAF2-dependent mitophagy. The goals of this proposal are to determine the mechanisms of: ZFAND6 regulation of mitophagy (Aim 1), ZFAND6 regulation of inflammation (Aim 2) and ZFAND6 regulation of the NLRP3 inflammasome (Aim 3). We anticipate that completion of these studies will provide new insight into the mechanisms underlying the regulation of mitophagy, inflammation and immune homeostasis.
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