| Gene Symbol | HUWE1 |
| Full Name | HECT, UBA and WWE Domain Containing E3 Ubiquitin Protein Ligase 1 |
| Aliases | ARF-BP1, MULE, LASU1, UREB1 |
| Chromosome | Xp11.22 |
| NCBI Gene ID | 10075 |
| OMIM | 300697 |
| Ensembl | ENSG00000086758 |
| UniProt | Q7Z6Z7 |
| Associated Diseases | X-linked intellectual disability, Alzheimer's disease, Parkinson's disease |
HUWE1 encodes one of the largest human E3 ubiquitin ligases (~482 kDa), a HECT-domain enzyme that ubiquitinates a broad spectrum of substrates controlling cell proliferation, apoptosis, DNA damage response, and protein quality control. In the nervous system, HUWE1 is a master regulator of neuronal proteostasis, targeting misfolded proteins, regulating mitochondrial dynamics, controlling p53-mediated apoptosis, and modulating synaptic protein turnover. Mutations in HUWE1 cause X-linked intellectual disability syndromes, and its dysfunction is linked to protein aggregation pathologies in Alzheimer's disease and Parkinson's disease.
HUWE1 spans approximately 138 kb on chromosome Xp11.22 and contains 85 exons encoding a 4,374-amino-acid protein. As an X-linked gene, HUWE1 exhibits dosage sensitivity — hemizygous males are more vulnerable to loss-of-function variants. The gene is highly expressed in the brain throughout development and adulthood, with complex transcriptional regulation by Myc, E2F, and activity-dependent transcription factors[1].
HUWE1 is a central component of the neuronal ubiquitin-proteasome system. It recognizes and ubiquitinates misfolded and damaged proteins for proteasomal degradation, preventing inclusion body formation by rapidly ubiquitinating aggregation-prone species. HUWE1 generates K48-linked polyubiquitin chains for proteasomal targeting and K63-linked chains for signaling and autophagic targeting[2].
HUWE1 ubiquitinates several proteins central to neurodegeneration: MCL-1 (anti-apoptotic BCL-2 family member whose HUWE1-mediated degradation sensitizes neurons to apoptosis), p53 (HUWE1 as ARF-BP1 is a major p53 E3 ligase), MFN2 (mitofusin-2, whose HUWE1 ubiquitination regulates mitochondrial fusion-fission balance), Myc (proto-oncogene controlling neuronal proliferation), and DDIT4/REDD1 (mTOR pathway inhibitor whose HUWE1-mediated degradation activates mTOR)[3].
HUWE1 regulates mitochondrial dynamics through ubiquitination of mitofusin-2 (MFN2). It promotes mitochondrial fission under stress conditions, facilitates mitophagy by enabling PINK1 accumulation on damaged mitochondria, coordinates with MARCH5 for outer mitochondrial membrane protein ubiquitination, and is essential for mitochondrial network remodeling during neuronal stress[4].
HUWE1 participates in the neuronal DNA damage response by ubiquitinating and degrading base excision repair intermediate POLB (DNA polymerase beta), modulating p53 stability to balance DNA repair with apoptosis decisions, and regulating histone H2AX ubiquitination at double-strand breaks. Post-mitotic neurons with impaired DNA repair are especially dependent on HUWE1 for damage management[5].
At the synapse, HUWE1 regulates activity-dependent protein degradation, synaptic vesicle protein turnover, postsynaptic density remodeling, and long-term plasticity through targeted substrate degradation[6].
Mutations in HUWE1 cause several X-linked intellectual disability syndromes including Turner syndrome type (OMIM 309590, missense mutations causing intellectual disability and macrocephaly), Juberg-Marsidi syndrome (more severe, with growth retardation and deafness), and Brooks syndrome (intellectual disability with growth restriction). These demonstrate HUWE1's essential role in neurodevelopment[7].
HUWE1 dysfunction contributes to AD through MCL-1 accumulation (resistance to apoptosis paradoxically prevents clearance of damaged neurons), impaired proteostasis (reduced ability to clear misfolded tau and amyloid-beta precursors), p53 dysregulation (aberrant p53 stabilization triggers neuronal cell cycle re-entry and death), and mitochondrial network fragmentation (excessive MFN2 ubiquitination disrupts mitochondrial function)[8].
HUWE1 intersects with PD pathways through the PINK1/Parkin pathway (HUWE1-mediated MFN2 ubiquitination coordinates with Parkin-mediated mitophagy), alpha-synuclein clearance (HUWE1 contributes to ubiquitination of misfolded alpha-synuclein species), and dopaminergic neuron vulnerability (high metabolic demands make SNc neurons dependent on HUWE1-mediated quality control)[4:1].
HUWE1 shows high and widespread brain expression in cortical neurons (protein quality control), hippocampal neurons (synaptic turnover regulation), dopaminergic neurons (mitochondrial quality control), and Purkinje cells (large soma requiring robust proteostasis).
Allen Human Brain Atlas: HUWE1 expression
Therapeutic strategies include HUWE1 activity modulators to enhance catalytic activity and boost aggregate clearance, substrate-specific approaches to selectively enhance degradation of specific aggregation-prone proteins, MCL-1/p53 axis targeting to fine-tune the apoptosis threshold in degenerating neurons, and modulating the HUWE1-MFN2 axis to optimize mitochondrial quality.
Zhong Q et al. Mule/ARF-BP1, a BH3-only E3 ubiquitin ligase, catalyzes the polyubiquitination of Mcl-1 and regulates apoptosis. Cell. 2005. ↩︎
Chen D et al. ARF-BP1/Mule is a critical mediator of the ARF tumor suppressor. Cell. 2005. ↩︎
Zhao X et al. The HECT-domain ubiquitin ligase Huwe1 controls neural differentiation and proliferation by destabilizing the N-Myc oncoprotein. Nature Cell Biology. 2008. ↩︎
Leboucher GP et al. Stress-induced phosphorylation and proteasomal degradation of mitofusin 2 facilitates mitochondrial fragmentation and apoptosis. Molecular Cell. 2012. ↩︎ ↩︎
Parsons JL et al. Ubiquitin ligase ARF-BP1/Mule modulates base excision repair. EMBO Journal. 2009. ↩︎
Bhm FD. Regulated proteolysis in learning-related synaptic plasticity. Biochimica et Biophysica Acta. 2014. ↩︎
Friez MJ et al. HUWE1 mutations in Juberg-Marsidi and Brooks syndromes: the results of an X-chromosome exome sequencing study. BMJ Open. 2016. ↩︎
Gong Y et al. Ubiquitin ligase HUWE1 regulates neuronal proteostasis. Acta Neuropathologica Communications. 2021. ↩︎