KCTD10 Biology: An Adaptor for the Ubiquitin E3 Complex Meets Multiple Substrates

Abstract

Protein ubiquitination constitutes a post‐translational modification mediated by ubiquitin ligases whereby ubiquitinated substrates are degraded through the proteasomal or lysosomal pathways, or acquire novel molecular functions according to their “ubiquitin codes.” Dysfunction of the ubiquitination process in cells causes various diseases such as cancers along with neurodegenerative, auto‐immune/inflammatory, and metabolic diseases. KCTD10 functions as a substrate recognition receptor for cullin‐3 (CUL3), a scaffold protein in RING‐type ubiquitin ligase complexes. Recently, studies by ourselves and others have identified new substrates that are ubiquitinated by the CUL3/KCTD10 ubiquitin ligase complex. Moreover, the type of polyubiquitination (e.g., K27‐, K48‐, or K63‐chain) of various substrates (e.g., RhoB, CEP97, EIF3D, and TRIF) mediated by KCTD10 underlies its divergent roles in endothelial barrier formation, primary cilium formation, plasma membrane dynamics, cell proliferation, and immune response. Here, the physiological functions of KCTD10 are summarized and potential mechanisms are proposed.

CNKSR1 serves as a scaffold to activate an EGFR phosphatase via exclusive interaction with RhoB-GTP

“…In such complexes, a substrate recognition receptor, specifically a BTB domain-containing protein (BTBP), recruits substrates leading to their ubiquitination ( Petroski & Deshaies, 2005 ). One BTBP, KCTD10, recognizes various substrates (e.g., RhoB, CEP97, EIF3D, TRIF, and EPS8) ( Kovačević et al, 2018 ; Nagai et al, 2018 ; Maekawa et al, 2019 ; Murakami et al, 2019 ; Wu et al, 2019 ; Maekawa & Higashiyama, 2020 ; Rodríguez-Pérez et al, 2021 ). We previously reported that the constitutive degradation of an endosomal small GTPase RhoB by the CUL3/KCTD10 E3 complex functions in EGF-induced Rac1 activation specifically in HER2-positive breast cancer cell lines, among other breast cancer subtypes ( Murakami et al, 2019 ).…”

The CRL3 KCTD10 ubiquitin ligase–USP18 axis coordinately regulates cystine uptake and ferroptosis by modulating SLC7A11

“…2 D ), indicating that the first 43 amino acids of SLC7A11 mediate KCTD10 binding. We then defined the KCTD10 binding domain on SLC7A11 by constructing two mutants: a BTB delete mutant (KCTD10ΔBTB) which fails to binds to Cul-3 and a C-terminal delete mutant (KCTD10ΔC), which fails to bind to substrate ( 23 , 24 ) ( SI Appendix , Fig. S2 B ).…”

“…Our conclusion is supported by the following lines of evidence: 1) pharmacological inhibition of neddylation or siRNA-based knockdown of Cul-3 causes SLC7A11 accumulation; 2) KCTD10 binds to SLC7A11 via its C-terminal region and SLC7A11 interacts with KCTD10 via its N-terminal domain; 3) KCTD10 overexpression or knockdown decreases or increases SLC7A11 levels, respectively; 4) KCTD10 overexpression or knockdown shortens or extends SLC7A11 protein half-life, respectively; 5) KCTD10 promotes SLC7A11 ubiquitylation for proteasome degradation. Thus, our study adds SLC7A11 to the repertoire of the growing list of KCTD10 substrates ( 23 ).…”

The Roles of SPOP in DNA Damage Response and DNA Replication

“…Humans possess eight CUL proteins, CUL1, CUL2, CUL3, CUL4A, CUL4B, CUL5, CUL7, and CUL9 [11]. The CUL3/RING ubiquitin E3 complex consists of CUL3, substrate recognizing receptors (Bric-à-brac/Tramtrack/Broad complex domain-containing proteins (BTBPs), E2, and E3s (RBX1, ARIH1, DCNLs) [12,13]. BTBPs recognize their substrate proteins and interact with the N-terminus of CUL3, leading to their ubiquitination [14].…”