HACE1 (HECT domain and ankyrin repeat containing E3 ubiquitin protein ligase 1)

	Schematic structure of the HACE1 protein. HACE1 contains six ankyrin repeats at the N terminus and a HECT domain at the C terminus. A cysteine residue essential for the ubiquitin ligase activity is at position 876.
Description	Human HACE1 encodes HACE1 protein, which containing 909 amino acid residues (size ~103 kDa) (Anglesio et al., 2004). HACE1 possesses six N-terminal ankyrin repeats (amino acid: 64-93; 97-126; 130-159; 163-192; 196-227; 228-257) and a C-terminal HECT domain (amino acid: 572-909; active cysteine residue at position 876).
Expression	Anglesio et al. showed that a 4,6-kb transcript of HACE1 with strong expression in heart, brain, placenta, pancreas, as well as adult and fetal kidney. HACE1 expression is virtually undetectable in the SK-NEP-1 Wilms' tumor cell line and in four of five additional primary Wilms' tumor cases compared with patient-matched normal kidney (Anglesio et al., 2004). Zhang et al. showed that HACE1 mRNA transcripts are ubiquitously expressed in normal human tissues; but the mRNA expression of HACE1 decreases markedly in breast, renal, thyroid, vulva and liver tumors compared to the organ-matched normal tissue samples from the same individuals. The transcripts are downregulated in almost all lines from the NCI-60 panel of human cancer cell lines compared to control HEK293 cells. Lower expression is strongly associated with hypermethylation of two CpG islands located upstream of the HACE1 locus (Zhang et al., 2007). HACE1 is also downregulated in natural killer/T-cell lymphoma of the nasal type (NKTCL) (Huang et al., 2010), colorectal cancer (Hibi et al., 2008) and gastric cancer (Sakata et al., 2009). However, the expression of HACE1 varies in different breast cancer cell lines (Kao et al., 2009). In neuroblastomas, low HACE1 expression is associated with worse overall survival, suggesting that HACE1 may function as a tumor suppressor (Diskin et al., 2012).
Localisation	Anglesio et al. indicated that the subcellular localization of HACE1 is predominantly in the endoplasmic reticulum (ER) and cytosol, and a small amount of endogenous protein is also present in other fractions of NIH3T3 cells (Anglesio et al., 2004). Tang et al. showed that a fraction of HACE1 colocalizes with Golgi markers in HeLa and normal rat kidney (NRK) cells; the association of HACE1 with Golgi membranes is through interaction with Golgi Rab GTPases, in particular Rab1 (Tang et al., 2011).
Function	Tumor suppressor Anglesio et al. showed that HACE1 possesses intrinsic ubiquitin ligase activity, utilizing UBCH7 as a candidate partner E2 enzyme (Anglesio et al., 2004). Zhang et al. demonstrated that HACE1 is frequently downregulated in human tumors and maps to a region of chromosome 6q21 implicated in multiple human cancers. Genetic inactivation of HACE1 in mice resulted in the development of spontaneous, late-onset cancer. Their data suggested that HACE1 is involved in phosphorylation dependent degradation of cyclin D1, indicating a role for HACE1 in inhibiting cell cycle progression (Zhang et al., 2007). HACE1 deficient mice are spontaneously prone to developing multiple malignant tumors in various organs (Zhang et al., 2007). Degradation of Rac1 In 2011, Torrino et al. reported that HACE1 binds preferentially GTP-bound Rac1 and catalyzes its polyubiquitination. HACE1 expression increases the ubiquitination of Rac1 when the GTPase is activated. HACE1 is required for cytotoxic necrosis factor 1 (CNSF1)-mediated depletion of Rac1 and efficient invasion of endothelial cell monolayer by bacteria, suggesting that HACE1 plays a major role in host defense against pathogens (Torrino et al., 2011). Castillo-Lluva et al. further showed that HACE1 catalyzes polyubiquitination of Rac1 at lysine 147 following its activation by a migration stimulus, such as hepatocyte growth factor (HGF), resulting in Rac1 degradation by the proteasome. HACE1-depletion is accompanied by an increased total Rac1 level and accumulation of Rac1 in membrane ruffles. Furthermore, HACE1-depletion leads to enhanced cell migration, which may be significant for malignant conversion (Castillo-Lluva et al., 2012). Golgi biogenesis Tang et al. reported that HACE1 is targeted to the Golgi membrane through interactions with Rab proteins. The ubiquitin ligase activity of HACE1 in mitotic Golgi disassembly is required for subsequent post-mitotic Golgi membrane fusion. Depletion of HACE1 using small hairpin RNAs or expression of an inactive HACE1 mutant protein in cells impairs post-mitotic Golgi membrane fusion. The identification of HACE1 as a Golgi-localized ubiquitin ligase provides evidence that ubiquitin has a critical role in Golgi biogenesis during the cell cycle (Tang et al., 2011). Repression of the RAR (retinoic acid receptor)-regulated transcription HACE1 was isolated as a RARβ3 AB region interacting protein. HACE1 functionally represses the transcriptional activity of RARα1 and RARβ isoforms 1, 2 and 3, but not RARγ1 in luciferase reporter assays. In addition, HACE1 represses several endogenous RAR-regulated genes. The E3 ubiquitin ligase activity is not required for the repression effect of HACE1 on the transcriptional activity of RARβ3. HACE1 also inhibits the retinoic acid-dependent degradation of RARβ3. The repression of RAR-regulated transcription by HACE1 is possibly due to its ability to inhibit RA-induced degradation of RARs (Zhao et al., 2009). Determinant of the equol-producing phenotype HACE1 was identified in a genome-wide association study (GWAS) designed to find genetic factors associated with the equol-producing phenotype in Korean population. The authors identified 5 single-nucleotide polymorphisms in HACE1. Individuals with a minor allele of the most significant SNP rs6927608 did not produce equol. The interaction between equol production and the rs6927608 HACE1 SNP was significantly associated with systolic blood pressure. Finally, the authors concluded that equol production is linked to blood pressure, and HACE1 might be a determinant of the equol-producing phenotype (Hong et al., 2012).
Homology	The HACE1 gene is conserved in chimpanzee, dog, cow, mouse, rat, chicken, and zebrafish.

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