Cullin-3-RING ligase complex with Kelch repeat and BTB domain-containing protein 4 substrate receptor (CRL3^KBTBD4)

The Cullin-3-RING ligase complex with Kelch repeat and BTB domain-containing protein 4 substrate receptor (CRL3^KBTBD4) is a multi-subunit E3 ubiquitin ligase that plays a critical role in protein homeostasis and epigenetic regulation (1.1.1, 1.2.1). KBTBD4 serves as the substrate-specific adapter, utilizing its BTB domain to bind the Cullin-3 scaffold and its Kelch domain to recruit targets for ubiquitination (1.2.1, 1.3.2). In its wild-type state, the complex regulates specific cellular substrates, but recurrent in-frame insertion/deletion (indel) mutations in the KBTBD4 Kelch domain act as primary drivers in Group 3 and Group 4 medulloblastoma (1.1.2, 1.2.2). These mutations confer a neomorphic gain-of-function, enabling the ligase to recruit and degrade the CoREST transcriptional repressor complex, which includes LSD1 and HDAC1/2 (1.2.3, 1.2.5). This aberrant degradation leads to epigenetic rewiring, increased histone H3K4 methylation, and the activation of stemness-related genes that promote tumor progression (1.2.1, 1.3.2). Interestingly, the small molecule UM171 acts as a molecular glue that mimics these oncogenic mutations by inducing the same neomorphic interaction between wild-type KBTBD4 and the CoREST complex (1.2.4, 1.2.5). Conversely, HDAC inhibitors have been shown to disrupt the interaction between mutant KBTBD4 and its neo-substrates, suggesting a potential therapeutic vulnerability for KBTBD4-driven cancers (1.3.1, 1.3.3).

Other names

KBTBD4 E3 ubiquitin ligase complexCUL3-KBTBD4 complexKelch repeat and BTB domain-containing protein 4 E3 ligaseCRL3-KBTBD4

Neomorphic recruitment and degradation of the CoREST complex (LSD1-HDAC1/2-CoREST) via molecular glue interaction or oncogenic mutation.