HACE1

This gene encodes a HECT domain and ankyrin repeat-containing ubiquitin ligase. The encoded protein is involved in specific tagging of target proteins, leading to their subcellular localization or proteasomal degradation. The protein is a potential tumor suppressor and is involved in the pathophysiology of several tumors, including Wilm's tumor.

HECT domain and ankyrin repeat containing, E3 ubiquitin protein ligase 1

E3 ubiquitin-protein ligase involved in Golgi membrane fusion and regulation of small GTPases. 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. Acts by mediating ubiquitination during mitotic Golgi disassembly, ubiquitination serving as a signal for Golgi reassembly later, after cell division. Specifically interacts with GTP-bound RAC1, mediating ubiquitination and subsequent degradation of active RAC1, thereby playing a role in host defense against pathogens. May also act as a transcription regulator via its interaction with RARB.

Cell cycle Source: UniProtKB-KW
Golgi organization Source: UniProtKB
Membrane fusion Source: UniProtKB
Positive regulation of protein catabolic process Source: GO_Central
Proteasome-mediated ubiquitin-dependent protein catabolic process Source: GO_Central
Protein K48-linked ubiquitination Source: UniProtKB
Protein polyubiquitination Source: GO_Central
Protein ubiquitination Source: UniProtKB
Rac protein signal transduction Source: UniProtKB
Regulation of cell migration Source: UniProtKB
Ubiquitin-dependent protein catabolic process Source: UniProtKB

Golgi stack membrane; Endoplasmic reticulum; Cytoplasm. A significant portion localizes to the endoplasmic reticulum. Targeted to Golgi membrane via its interaction with Rab proteins.

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.