CUL3

CUL3 Full Name

cullin 3

CUL3 Introduction

CUL3 (cullin 3) is a highly conserved scaffold protein that forms the core of the Cullin-RING E3 ubiquitin ligase complex (CRL3), a system responsible for recognizing and directing numerous intracellular proteins toward ubiquitin-mediated degradation. Researchers often face challenges in understanding how alterations in protein turnover contribute to disease progression, and CUL3 has emerged as a central regulator linking protein quality control to cellular homeostasis. Through interactions with BTB-domain adaptor proteins, including LZTR1, KLHL family members, and KCTD proteins, CUL3 governs the stability of substrates involved in cell cycle progression, oxidative stress responses, signal transduction, and cytoskeletal organization. Increasing evidence from recent studies has highlighted that disruption of CUL3-dependent ubiquitination leads to widespread disturbances in cellular signaling networks, making CUL3 an important target in oncology, neuroscience, and cardiovascular research.

Functionally, CUL3 exerts its biological effects by assembling substrate-specific E3 ligase complexes that regulate diverse pathways essential for tissue development and physiological balance. One of the most extensively characterized mechanisms involves the LZTR1-CUL3 complex, which mediates ubiquitination of members of the RAS superfamily, including RAS, RHEB, and RAP1B, thereby modulating the RAS/MAPK signaling cascade. Loss of CUL3 activity or defective adaptor recruitment can result in excessive pathway activation, promoting abnormal cell proliferation and developmental abnormalities. In addition, CUL3 plays a pivotal role in maintaining redox homeostasis through regulation of the KEAP1-NRF2 axis, while also controlling vascular tone and renal electrolyte transport by targeting WNK kinases, RhoA, and phosphodiesterases. In the nervous system, CUL3-dependent protein degradation contributes to neuronal morphogenesis, synaptic function, and excitatory-inhibitory balance, underscoring its importance during critical stages of brain development.

Accumulating clinical and genetic evidence has linked CUL3 dysfunction to a broad spectrum of human diseases. Germline mutations and deletions affecting CUL3 or its adaptor proteins have been associated with neurodevelopmental disorders, particularly autism spectrum disorder, intellectual disability, developmental delay, epilepsy, and behavioral abnormalities. CUL3 abnormalities are also implicated in tumorigenesis, with defective LZTR1-CUL3 signaling contributing to schwannomatosis, Noonan syndrome, glioblastoma, and other malignancies through deregulation of RAS signaling. In cardiovascular and renal medicine, pathogenic variants such as exon 9 deletion mutants disrupt CRL3 activity and lead to familial hyperkalemic hypertension (FHHt), characterized by hypertension, hyperkalemia, metabolic acidosis, vascular stiffness, and systemic complications. Recent reviews further suggest that CUL3-associated disorders should be viewed as multisystem diseases rather than isolated organ-specific conditions. Owing to its central role in ubiquitin-mediated proteostasis and multiple disease-driving pathways, CUL3 has gained considerable attention as a promising therapeutic target and a valuable biomarker for precision medicine and targeted drug development.

Alternate Names for CUL3

CUL3; cullin 3; CUL-3; PHA2E; cullin-3; cullin3

• 1.Zhang H, et al.; LZTR1: A promising adaptor of the CUL3 family. Oncol Lett. 2021, 22(1):564.
  2.Lin P, et al.; Current trends of high-risk gene Cul3 in neurodevelopmental disorders. Front Psychiatry. 2023, 14:1215110.