USP6 Gene: Function, Mutations, and Role in Aneurysmal Bone Cyst

USP6 (Ubiquitin Specific Peptidase 6) encodes a deubiquitinating enzyme that removes ubiquitin from target proteins, thereby regulating protein stability and signaling pathways. It is a well-established oncogene, frequently activated by chromosomal rearrangements that lead to its overexpression. USP6 fusions are a hallmark of primary aneurysmal bone cyst (ABC) and nodular fasciitis, and are also found in other benign and malignant neoplasms.

Tissue Expression

Cell Line Expression

Hotspot Mutations

Mutation functional classification

• Ubiquitin-proteasome system

• RANKL signaling (osteoclastogenesis)

• MAPK signaling (via USP6-mediated stabilization of signaling intermediates)

USP6 (Ubiquitin Specific Peptidase 6) is a 1406-amino acid deubiquitinating enzyme that cleaves ubiquitin from target proteins, thereby preventing their proteasomal degradation. It contains an N-terminal Tre2 domain and a C-terminal catalytic USP domain. USP6 is normally expressed at very low levels in most adult tissues, but is highly overexpressed in certain tumors due to promoter swapping from gene fusions. Overexpressed USP6 stabilizes proteins involved in cell growth and osteoclast differentiation, such as MMP9 and NFATc1, contributing to the pathogenesis of aneurysmal bone cyst and nodular fasciitis.