KLHL22 (kelch like family member 22) functions as a substrate adapter for the CUL3-based E3 ubiquitin ligase complex (BCR(KLHL22)), orchestrating multiple cellular processes through selective protein ubiquitination. Its primary role involves regulating mitotic progression by mediating monoubiquitination of PLK1 at Lys492 within the polo-box domain, causing PLK1 dissociation from kinetochores and enabling spindle assembly checkpoint silencing without triggering PLK1 degradation 1. KLHL22 also activates mTORC1 signaling by promoting K48-linked polyubiquitination and proteasomal degradation of DEPDC5, a key GATOR1 complex component, thereby releasing mTORC1 inhibition in response to amino acid stimulation 2. The BCR(KLHL22) complex achieves its catalytic activity through a conserved CUL3 N-terminal motif that enables dimeric assembly and creates a variable ubiquitination zone for substrate recognition 3. Beyond cell cycle and nutrient sensing, KLHL22 regulates immune homeostasis by maintaining PD-1 protein stability through ubiquitin-mediated degradation prior to surface transport, preventing excessive T cell suppression 4. KLHL22 also mediates degradation of NSP6 viral protein, controlling calcium homeostasis and autophagic cell death in SARS-CoV-2 infection 5. Elevated KLHL22 correlates with breast cancer progression and poor prognosis, making it a potential therapeutic target 2.