UBIQUITIN CARBOXYL-TERMINAL HYDROLASE L5; UCHL5

Alternative titles; symbols

• UCH37

HGNC Approved Gene Symbol: UCHL5

Cytogenetic location: 1q31.2 Genomic coordinates (GRCh38): 1:193,012,253-193,060,139 (from NCBI)

▼ Cloning and Expression

Using yeast 2-hybrid analysis of a mouse brain library with the N-terminal region of Smad3 (603109) as bait, Wicks et al. (2005) identified mouse Uchl5. They stated that mouse Uchl5 and human UCH37 (UCHL5) are 99% identical. UCHL5 is a member of the UCH enzyme family and contains a conserved catalytic domain and a nonconserved extended C-terminal tail.

▼ Gene Function

Lam et al. (1997, 1997) originally identified bovine UCHL5 as a component of the 26S proteasome and showed that it functions in editing polyubiquitinated protein substrates.

Wicks et al. (2005) reported that proteasome-associated UCHL5 sequentially removes ubiquitin from the distal end of the lys48-linked polyubiquitin chain and has the potential to rescue ubiquitinated substrates from proteasomal degradation. Using a variety of immunoprecipitation assays, they found that mouse Uchl5 binds strongly to Smad7 (602932) and weakly to Smad2 (601366) and Smad3. Deletion constructs showed that Uchl5 binding does not require the Smurf-binding PY motif of Smad7. Transfection experiments with transforming growth factor-beta receptor-1 (Tgfbr1; 190181), Smad7, Smurf2 (605532), and Uchl5 showed that Uchl5 deubiquitinates and stabilizes TGFBR1. Using a luciferase reporter construct in HEK-293 cells, Wicks et al. (2005) showed that Uchl5 overexpression increases Tgfbr1-dependent transcription. Knockdown of Uchl5 expression by RNA interference abrogated Tgf-beta-dependent transcription.

Rolen et al. (2006) reported that deregulation of some ubiquitin-specific proteases (USPs) affect tumor growth. Using a functional proteomics assay in which tagged probes target the active sites of USPs, they investigated the activity of USPs in human HPV-carrying cervical carcinoma biopsies relative to adjacent normal tissue. The activity of UCHL5 was significantly increased in 76% of the tumors analyzed. UCHL5 was active in 92% (24 of 26) of the cervical carcinoma biopsies, and in 100% of 8 cervical carcinoma cell lines, of which 6 were HPV-positive and 2 were HPV-negative. UCHL5 activity level did not correlate with the clinical stage of the tumors or the presence of metastases.

▼ Mapping

The International Radiation Hybrid Mapping Consortium mapped the UCHL5 gene to chromosome 1 (WI-14924).