HACE1
Developmental stage
Expressed in fetal and pediatric kidney cells.
Domain
The N-terminal lobe of the HECT domain is important for interaction with E2 ubiquitin-conjugating enzymes.
The ANK repeats ANK 3, ANK 4 and ANK 5 are important for recognizing the RAC1 substrate.
Function
E3 ubiquitin-protein ligase involved in Golgi membrane fusion and regulation of small GTPases (PubMed:15254018, PubMed:21988917, PubMed:22036506, PubMed:37537642, PubMed:38332367). Acts as a regulator of Golgi membrane dynamics during the cell cycle: recruited to Golgi membrane by Rab proteins and regulates postmitotic Golgi membrane fusion (PubMed:21988917). Acts by mediating ubiquitination during mitotic Golgi disassembly, ubiquitination serving as a signal for Golgi reassembly later, after cell division (PubMed:21988917). Specifically binds GTP-bound RAC1, mediating ubiquitination and subsequent degradation of active RAC1, thereby playing a role in host defense against pathogens (PubMed:22036506, PubMed:37537642, PubMed:38332367). May also act as a transcription regulator via its interaction with RARB (By similarity).
Involvement in disease
Defects in HACE1 are a cause of Wilms tumor (WT). WT is a pediatric malignancy of kidney and one of the most common solid cancers in childhood. HACE1 is epigenetically down-regulated in sporadic Wilms tumor. Moreover, a t(5;6)(q21;q21) translocation that truncates HACE1 has been found in a child with bilateral, young-onset Wilms tumor (PubMed:19948536).
Spastic paraplegia and psychomotor retardation with or without seizures
SPPRS
A form of spastic paraplegia, a neurodegenerative disorder characterized by a slow, gradual, progressive weakness and spasticity of the lower limbs. Rate of progression and the severity of symptoms are quite variable. Initial symptoms may include difficulty with balance, weakness and stiffness in the legs, muscle spasms, and dragging the toes when walking. In some forms of the disorder, bladder symptoms (such as incontinence) may appear, or the weakness and stiffness may spread to other parts of the body. SPPRS is an autosomal recessive neurodevelopmental disorder manifesting in infancy. Affected individuals show hypotonia and psychomotor retardation. Most develop seizures.
None
The disease is caused by variants affecting the gene represented in this entry.
Pathway
Protein modification; protein ubiquitination.
Post-translational modifications
Autoubiquitinated.
Tissue Specificity
Expressed in multiple tissues including heart, brain and kidney.
Cellular localization
- Golgi apparatus
- Golgi stack membrane
- Cytoplasm
- Endoplasmic reticulum
- A significant portion localizes to the endoplasmic reticulum. Targeted to Golgi membrane via its interaction with Rab proteins.
Alternative names
KIAA1320, HACE1, E3 ubiquitin-protein ligase HACE1, HECT domain and ankyrin repeat-containing E3 ubiquitin-protein ligase 1, HECT-type E3 ubiquitin transferase HACE1