Zfand6, also known as AWP1, is a zinc finger protein that interacts with TNF receptor-associated factor 2 (TRAF2) and polyubiquitin chains, being linked to TNF signaling. It plays a crucial role in maintaining mitochondrial homeostasis by promoting mitophagy [1]. It also functions in Pex5 export during peroxisome biogenesis by interacting with cys-monoubiquitinated Pex5 and Pex6 AAA ATPase [2]. Additionally, Zfand6 has been associated with type 2 diabetes, prediabetes, and may play roles in sperm function and trophoblast cell apoptosis, as well as being related to high myopia [3-6].

Deletion of ZFAND6 in bone marrow-derived macrophages (BMDMs) impairs mitophagy, leading to increased reactive oxygen species (ROS), damaged mitochondria accumulation, mitochondrial DNA (mtDNA) release into the cytoplasm, and spontaneous expression of interferon-stimulated genes (ISGs) in a STING-dependent manner, enhancing viral resistance [1]. In breast cancer cells, AWP1/ZFAND6 knockdown increases migratory potential in response to TNF-α, suggesting it restrains the aggressive behavior of these cells [3].

In conclusion, Zfand6 is essential for maintaining mitochondrial homeostasis through promoting mitophagy and has implications in various disease areas such as diabetes, infertility, and high myopia. Studies, especially those using loss-of-function models like the deletion in BMDMs, have revealed its diverse roles in biological processes and disease conditions, providing insights into potential therapeutic targets and disease mechanisms [1, 3-6].

References:

1. Shaikh, Kashif, Bowman, Melissa, McCormick, Sarah M, Norbury, Christopher C, Harhaj, Edward W. 2024. ZFAND6 promotes TRAF2-dependent mitophagy to restrain cGAS-STING signaling. In iScience, 28, 111544. doi:10.1016/j.isci.2024.111544. https://pubmed.ncbi.nlm.nih.gov/39811672/

2. Miyata, Non, Okumoto, Kanji, Mukai, Satoru, Noguchi, Masafumi, Fujiki, Yukio. 2011. AWP1/ZFAND6 functions in Pex5 export by interacting with cys-monoubiquitinated Pex5 and Pex6 AAA ATPase. In Traffic (Copenhagen, Denmark), 13, 168-83. doi:10.1111/j.1600-0854.2011.01298.x. https://pubmed.ncbi.nlm.nih.gov/21980954/

3. Kim, Eun-Young, Kim, Ji-Eun, Choi, Bongkun, Kim, Yongsub, Chang, Eun-Ju. 2021. AWP1 Restrains the Aggressive Behavior of Breast Cancer Cells Induced by TNF-α. In Frontiers in oncology, 11, 631469. doi:10.3389/fonc.2021.631469. https://pubmed.ncbi.nlm.nih.gov/33816268/