CALCOCO2, also known as NDP52 (nuclear dot 10 protein 52), is an autophagy receptor that plays a crucial role in various autophagy-related processes. It is involved in pathways such as mitophagy, the selective autophagic degradation of mitochondria, and other lysosomal degradation pathways. These functions are essential for maintaining cellular homeostasis, and genetic models like gene knockout (KO) mouse models can be valuable in studying its functions [2,3,4].

In a study on hepatitis B virus (HBV) infection, CALCOCO2 was found to target HBV envelope proteins to the lysosome for degradation, inhibiting viral replication. This process depends on RAB9 and is distinct from anti-bacterial autophagy as it doesn't require LGALS8 or ATG5 [1]. In the context of mitophagy, CALCOCO2, along with OPTN, can initiate de novo biogenesis of autophagic membranes on ubiquitin-coated damaged mitochondria through the CALCOCO2-RB1CC1 axis, highlighting its critical role in mitochondrial degradation [2]. In a model of atrial fibrillation (AF), overexpression of CALCOCO2 reversed AF-induced mitochondrial impairment, fibrosis, and oxidative stress by regulating mitophagy and mitochondrial stress, suggesting its potential as a target for AF therapy [3]. In coxsackievirus B3 (CVB3) infection, depletion of CALCOCO2 significantly inhibited viral growth, and it was shown to suppress the antiviral type I interferon signaling by promoting autophagy-mediated degradation of the mitochondrial antiviral signaling (MAVS) protein [5].

In summary, CALCOCO2 is a key autophagy receptor involved in mitophagy and other lysosomal degradation pathways. Studies using various models, including those related to HBV infection, mitochondrial function, AF, and CVB3 infection, have revealed its important roles in antiviral responses, mitochondrial homeostasis, and in disease-related processes such as atrial remodeling and viral propagation. These findings highlight the significance of CALCOCO2 in understanding autophagy-related biological functions and disease mechanisms.

References:

1. Cui, Shuzhi, Faure, Mathias, Wei, Yu. 2024. CALCOCO2/NDP52 associates with RAB9 to initiate an antiviral response to hepatitis B virus infection through a lysosomal degradation pathway. In Autophagy, 20, 2109-2111. doi:10.1080/15548627.2024.2353499. https://pubmed.ncbi.nlm.nih.gov/38752371/

2. Yamano, Koji, Youle, Richard J. 2020. Two different axes CALCOCO2-RB1CC1 and OPTN-ATG9A initiate PRKN-mediated mitophagy. In Autophagy, 16, 2105-2107. doi:10.1080/15548627.2020.1815457. https://pubmed.ncbi.nlm.nih.gov/32892694/

3. Sang, Wanyue, Yan, Xiaoji, Wang, Lu, Tang, Baopeng, Li, Yaodong. 2024. CALCOCO2 prevents AngII-induced atrial remodeling by regulating the interaction between mitophagy and mitochondrial stress. In International immunopharmacology, 140, 112841. doi:10.1016/j.intimp.2024.112841. https://pubmed.ncbi.nlm.nih.gov/39094358/

4. Sun, Kai, Jing, Xingzhi, Guo, Jiachao, Yao, Xudong, Guo, Fengjing. 2020. Mitophagy in degenerative joint diseases. In Autophagy, 17, 2082-2092. doi:10.1080/15548627.2020.1822097. https://pubmed.ncbi.nlm.nih.gov/32967533/

5. Mohamud, Yasir, Qu, Junyan, Xue, Yuan Chao, Deng, Haoyu, Luo, Honglin. 2018. CALCOCO2/NDP52 and SQSTM1/p62 differentially regulate coxsackievirus B3 propagation. In Cell death and differentiation, 26, 1062-1076. doi:10.1038/s41418-018-0185-5. https://pubmed.ncbi.nlm.nih.gov/30154446/