KLHL22

Full Name

Kelch Like Family Member 22

Function

Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin ligase complex required for chromosome alignment and localization of PLK1 at kinetochores. The BCR(KLHL22) ubiquitin ligase complex mediates monoubiquitination of PLK1, leading to PLK1 dissociation from phosphoreceptor proteins and subsequent removal from kinetochores, allowing silencing of the spindle assembly checkpoint (SAC) and chromosome segregation. Monoubiquitination of PLK1 does not lead to PLK1 degradation (PubMed:19995937, PubMed:23455478).
The BCR(KLHL22) ubiquitin ligase complex is also responsible for the amino acid-stimulated 'Lys-48' polyubiquitination and proteasomal degradation of DEPDC5. Through the degradation of DEPDC5, releases the GATOR1 complex-mediated inhibition of the TORC1 pathway. It is therefore an amino acid-dependent activator within the amino acid-sensing branch of the TORC1 pathway, indirectly regulating different cellular processes including cell growth and autophagy (PubMed:29769719).

Biological Process

Cell divisionManual Assertion Based On ExperimentIMP:UniProtKB
Cellular response to leucineManual Assertion Based On ExperimentIMP:UniProtKB
Mitotic sister chromatid segregationManual Assertion Based On ExperimentIMP:UniProtKB
Mitotic spindle assembly checkpoint signalingManual Assertion Based On ExperimentIMP:UniProtKB
Negative regulation of autophagyManual Assertion Based On ExperimentIMP:UniProtKB
Positive regulation of cell growthManual Assertion Based On ExperimentIMP:UniProtKB
Positive regulation of TORC1 signalingManual Assertion Based On ExperimentIMP:UniProtKB
Proteasome-mediated ubiquitin-dependent protein catabolic processManual Assertion Based On ExperimentIMP:UniProtKB
Protein monoubiquitinationManual Assertion Based On ExperimentIDA:UniProtKB

Cellular Location

Cytoplasm, cytosol; Cytoplasm, cytoskeleton, microtubule organizing center, centrosome; Cytoplasm, cytoskeleton, spindle; Nucleus; Lysosome. Mainly cytoplasmic in prophase and prometaphase. Associates with the mitotic spindle as the cells reach chromosome bi-orientation. Localizes to the centrosomes shortly before cells enter anaphase After anaphase onset, predominantly associates with the polar microtubules connecting the 2 opposing centrosomes and gradually diffuses into the cytoplasm during telophase (PubMed:23455478).
Localizes to the nucleus upon amino acid starvation (PubMed:29769719).
Relocalizes to the cytosol and associates with lysosomes when amino acids are available (PubMed:29769719).

Involvement in disease

Defects in KLHL22 has been found in a patient with isolated coloboma, a defect of the eye characterized by the absence of ocular structures due to abnormal morphogenesis of the optic cup and stalk, and the fusion of the fetal fissure (optic fissure). Isolated colobomas may be associated with an abnormally small eye (microphthalmia) or small cornea.