HUWE1

HUWE1 Full Name

HECT, UBA and WWE domain containing 1, E3 ubiquitin protein ligase

HUWE1 Introduction

HUWE1 (HECT, UBA and WWE domain containing E3 ubiquitin protein ligase 1, also known as ARF-BP1, MULE, LASU1, or HECTH9) is a large multidomain E3 ubiquitin ligase belonging to the HECT (homologous to the E6-AP carboxyl terminus) family. The gene is located on chromosome Xp11.22 and encodes a massive protein of 4,374 amino acids with a molecular weight of approximately 482 kDa, making it one of the largest E3 ligases in the human proteome. HUWE1 is ubiquitously expressed in all human tissues, with particularly high levels in the brain, heart, testis, and liver. As an E3 ubiquitin ligase, HUWE1 catalyzes the transfer of ubiquitin from an E2 ubiquitin-conjugating enzyme to specific substrate proteins, targeting them for proteasomal degradation or for functional modification. HUWE1 regulates a diverse array of substrates involved in critical cellular processes including DNA damage response, cell cycle progression, apoptosis, transcription, DNA replication, and chromatin remodeling. Given its broad substrate specificity and essential functions, HUWE1 has emerged as a key regulator of genome stability, neurodevelopment, and tumor suppression. Mutations and dysregulation of HUWE1 have been implicated in intellectual disability, X-linked mental retardation (XLMR), various cancers, and neurodegenerative disorders.

Figure 1. Schematic structure of HUWE1.

Biological Functions in DNA Damage Response and Cell Cycle Regulation
HUWE1 plays essential roles in the DNA damage response, cell cycle regulation, and apoptosis through the ubiquitination and degradation of key substrate proteins. A major substrate of HUWE1 is the tumor suppressor p53. HUWE1 ubiquitinates p53 at multiple lysine residues (including Lys-24, Lys-305, and Lys-321), targeting it for proteasomal degradation. Under normal conditions, HUWE1 maintains low p53 levels, preventing inappropriate p53 activation. In response to DNA damage, HUWE1 is inhibited, allowing p53 stabilization and activation, leading to cell cycle arrest and DNA repair. However, the regulation of p53 by HUWE1 is context-dependent; HUWE1 can also promote p53-mediated transcription under certain conditions. HUWE1 also ubiquitinates and degrades Mcl-1 (myeloid cell leukemia 1), an anti-apoptotic Bcl-2 family protein. By promoting Mcl-1 degradation, HUWE1 sensitizes cells to apoptosis, particularly in response to DNA damage and other stress signals. The BH3 domain of HUWE1 mediates direct interaction with Mcl-1, facilitating its ubiquitination. HUWE1 also regulates the stability of other cell cycle and apoptosis regulators including N-Myc, c-Myc, Cyclin D1, Cyclin E, Cdc6, and TopBP1. Through these substrates, HUWE1 controls cell cycle progression at multiple checkpoints, DNA replication initiation, and the G1/S transition. In the DNA damage response, HUWE1 is recruited to sites of DNA double-strand breaks through its interaction with poly(ADP-ribose) (PAR) chains via its WWE domains. At damage sites, HUWE1 ubiquitinates histones (particularly H2AX and H2B), promoting the recruitment of DNA repair factors and facilitating homologous recombination and non-homologous end joining (NHEJ). HUWE1 also ubiquitinates and regulates the stability of the DNA repair proteins BRCA1, 53BP1, and RAD51. Through these diverse functions, HUWE1 maintains genome stability and prevents the accumulation of damaged cells.

Pathophysiological and Clinical Significance of HUWE1
Genetic mutation, abnormal expression, or functional dysregulation of HUWE1 is closely associated with neurodevelopmental syndromes, hereditary diseases, and malignant tumors, exhibiting important clinical diagnostic and prognostic value in human disease research. In genetic disorders, germline mutations in the HUWE1 gene are the primary cause of Joubert syndrome, Mowat-Wilson syndrome, and multiple X-linked intellectual disability syndromes, characterized by abnormal brain development, cognitive impairment, and congenital organ malformations due to disrupted neuronal cell differentiation and genome stability. In human malignancies, HUWE1 displays dual context-dependent tumor regulatory functions. Aberrant overexpression of HUWE1 promotes tumor progression by degrading tumor suppressor proteins, accelerating cell cycle proliferation, and enhancing tumor cell survival in lung cancer, breast cancer, and colorectal cancer. Conversely, loss-of-function HUWE1 mutations contribute to genomic instability, driving tumor initiation and malignant transformation in liver cancer and hematological malignancies. Clinically, HUWE1 expression levels and mutation status are strongly correlated with tumor grade, metastasis potential, and patient survival outcomes, serving as a reliable prognostic biomarker and a novel targeted therapeutic candidate for precision disease intervention.

Alternate Names for HUWE1

HUWE1; HECT, UBA and WWE domain containing 1, E3 ubiquitin protein ligase; MULE; Ib772; LASU1; UREB1; HECTH9; URE-B1; ARF-BP1; HSPC272