Kelch-like protein 20 (KLHL20)

Kelch-like protein 20 (KLHL20) is a member of the BTB-Kelch protein family that acts as a substrate adaptor for a Cullin3-based E3 ubiquitin ligase complex[1][2][3][4]. KLHL20 uses its BTB and 3-box domains to recruit CUL3 and RBX1, forming a multi-subunit E3 ligase that targets specific substrates for polyubiquitination and proteasomal degradation. Key substrates include death-associated protein kinase 1 (DAPK1), promyelocytic leukemia protein (PML), and ULK1, impacting processes such as autophagy termination, apoptosis, tumor suppression, and stress responses[1][2]. KLHL20 is also induced under hypoxia, promoting tumor progression by degrading PML and supporting HIF-1α signaling[2]. In neurodegeneration, elevated KLHL20 expression serves as a biomarker for Alzheimer’s disease progression and may promote pathological protein accumulation by restricting autophagy[1]. Structural studies have identified potential small molecule binding sites on its Kelch domain, opening avenues for therapeutic intervention by inhibiting KLHL20-mediated degradation of tumor suppressors or autophagy regulators[1]. This protein is regarded as a bona fide therapeutic target and molecular adapter with key roles in ubiquitin-dependent proteolysis, autophagy regulation, and disease pathogenesis[1][2][3][4].

Other names

KLEIPkelch-like family member 20

Inhibition of substrate binding to the Kelch domain blocks ubiquitination and degradation of target proteins (such as DAPK1 and ULK1)