DDRGK1

Official Full Name

DDRGK domain containing 1

Organism

Homo sapiens

GeneID

65992

Background

The protein encoded by this gene interacts with components of the ubiquitin fold modifier 1 conjugation pathway and helps prevent apoptosis in ER-stressed secretory tissues. In addition, the encoded protein regulates nuclear factor-B activity. [provided by RefSeq, Dec 2015]

Synonyms

UFBP1; SEMDSH; C20orf116; dJ1187M17.3;

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Detailed Information

DDRGK1 (DDRGK domain containing 1), New evidence suggests that ER stress and mitochondrial dysfunction are closely associated with ROS production. Human DDRGK-containing domain protein 1 (DDRGK1) is a strongly conserved protein coding for the short arm of chromosome 20 (20p13) and localized to peroxisomes, mitochondria, and endoplasmic reticulum.

DDRGK1 Plays a Role in Endoplasmic Reticulum Homeostasis

DDRGK1 has been shown to play an essential role in endoplasmic reticulum homeostasis by regulating the stability of IRE1a, thus suggesting a potential role for DDRGK1 in the maintenance of redox homeostasis. To date, DDRGK1 has mostly been recognized as a substrate for UFMylation, which binds target proteins to ubiquitin fold modification factor 1 (UFM1). Despite its recently demonstrated role in UFMylation-mediated regulation of erythroid progression, spinal chondrodysplasia, and plasma cell development, the mechanisms by which DDRGK1 modulates UFMylation, as well as its other functions, remain largely unknown. Indeed, the identification of proteins interacting with DDRGK1 using label-free quantitative proteomics suggests that DDRGK1 is involved in the regulation of protein folding, stabilization, and trafficking.

DDRGK1 Plays a Role in Cell Growth

Deficiency of DDRGK1 leads to embryonic death in vivo, suggesting that it plays an integral role in cell growth, and most studies consider DDRGK1 to be a cytoprotective protein. However, the function of DDRGK1 in tumorigenesis and development remains controversial. For example, DDRGK1 interacts with and regulates the stability of IkBa, and its absence inhibits tumor cell proliferation. [In addition, by interacting with activation signaling integrator 1 (ASC1), DDRGK1 regulates UFMylation of ASC1 and promotes the development of ER-positive breast cancer. However, DDRGK1 has also been shown to maintain p53 stability and impair colon cancer growth by cooperating with UFM1 and covalently modifying p53. Covalent modification of p53. function in tumors in the absence of further research.

DDRGK1 Plays a Role in Regulating Cellular ROS Accumulation

Due to the fact that ROS are usually upregulated in tumor cells, tumor cells are heavily dependent on the antioxidant system to keep ROS effectively below lethal levels and are more susceptible to any damage that disrupts ROS homeostasis. Novel role for DDRGK1 in regulating the key ROS proteins, which compete with NRF2 for binding to the Kelch-like ECH-associated protein 1 (KEAP1), blocking the initiation of ubiquitin protease-mediated degradation by CUL3, the E3 ligase of NRF2, thereby broadly regulating the antioxidant system. DDRKG1 induced cellular ROS accumulation, leading to apoptosis and attenuation of DOX chemoresistance, which further inhibited tumor formation in vivo. Taken together, these results reveal a critical role for DDRGK1 in the KEAP1/NRF2/ROS pathway, which is instrumental in osteosarcoma development and chemoresistance.

The stability of NRF2 is critical for ROS homeostasis and is mainly degraded via the ubiquitin-proteasome pathway. KEAP1 acts as an adapter to link NRF2 to the CUL3-based E3 ligase. Hence, disrupting the interaction between NRF2 and KEAP1 or CUL3 may affect the degradation of NRF2. For instance, iASPP competes with NRF2 for KEAP1 binding through the DLT motif, resulting in reduced ubiquitination of NRF2. Similar to these studies, we also found that DDRGK1 can compete for binding to the Kelch domain of KEAP1, thereby blocking the interaction of NRF2 with CUL3 and inhibiting NRF2 degradation. ddrgk1 deletion induces NRF2 protein degradation and reduces the downstream expression of antioxidant proteins, which in turn induces ROS production.

Figure 1. Regulatory functions of DDRGK1 in the maintenance of ER homoeostasis.

References:

Wang X, Zhou T, Yang X, et al. DDRGK1 Enhances Osteosarcoma Chemoresistance via Inhibiting KEAP1-Mediated NRF2 Ubiquitination. Adv Sci (Weinh). 2023;10(14):e2204438. doi:10.1002/advs.202204438
Liu J, Wang Y, Song L, et al. A critical role of DDRGK1 in endoplasmic reticulum homoeostasis via regulation of IRE1α stability. Nat Commun. 2017;8:14186. Published 2017 Jan 27. doi:10.1038/ncomms14186

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