Dennd3, short for DENN domain-containing protein 3, functions as a guanine nucleotide exchange factor for the small GTPase Rab12. It is involved in crucial biological processes such as autophagy and is associated with the regulation of iron metabolism through the RAB12/TFR2 signaling pathway [1,2,3]. Genetic models, especially mouse models, have been instrumental in studying its functions.

In mouse embryonic fibroblasts, knockdown of Dennd3 led to an increase in the amount of PAT4 protein and intracellular amino acid concentration, similar to Rab12 knockdown [2]. However, Dennd3 knockdown unexpectedly had no effect on mTORC1 activity or autophagy, likely due to the reduction in Akt activity canceling out amino acid-induced mTORC1 activation. Overexpression of Dennd3 reduced mTORC1 activity and promoted autophagy in a Rab12-dependent manner. In vivo, mice infected with adeno-associated virus expressing the DENND3 p.L708V variant showed higher total serum iron concentrations, decreased HAMP level, increased iron accumulation, and down-regulated TFR2 expression in the liver [1].

In conclusion, Dennd3 is essential for autophagy regulation and iron metabolism. Mouse models, including knockdown and overexpression models, have revealed its role in autophagy-related pathways and in the pathogenesis of hereditary hemochromatosis. Understanding Dennd3 functions can provide insights into the underlying mechanisms of autophagy and iron-related disorders.

References:

1. Li, Yanmeng, Xu, Anjian, Ouyang, Qin, Jia, Jidong, Huang, Jian. 2023. DENND3 p.L708V activating variant is involved in the pathogenesis of hereditary hemochromatosis via the RAB12/TFR2 signaling pathway. In Hepatology international, 17, 648-661. doi:10.1007/s12072-022-10474-w. https://pubmed.ncbi.nlm.nih.gov/36729283/

2. Matsui, Takahide, Noguchi, Kenta, Fukuda, Mitsunori. 2014. Dennd3 functions as a guanine nucleotide exchange factor for small GTPase Rab12 in mouse embryonic fibroblasts. In The Journal of biological chemistry, 289, 13986-95. doi:10.1074/jbc.M113.546689. https://pubmed.ncbi.nlm.nih.gov/24719330/

3. Xu, Jie, McPherson, Peter S. 2017. Regulation of DENND3, the exchange factor for the small GTPase Rab12 through an intramolecular interaction. In The Journal of biological chemistry, 292, 7274-7282. doi:10.1074/jbc.M116.772434. https://pubmed.ncbi.nlm.nih.gov/28249939/