KLHL6

Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin ligase complex that acts as a multifunctional regulator of B-cell receptor (BCR) signaling, germinal center formation, and T-cell function. Functions by mediating polyubiquitination of target proteins, leading to their proteasomal degradation. In B-cells, plays an essential role in BCR signaling and germinal center B-cell maturation. Targets the BCR signaling subunits CD79A and CD79B for ubiquitin-mediated degradation, thereby controlling surface BCR homeostasis. Mediates polyubiquitination and degradation of the mRNA decay factor roquin-2/RC3H2, which in turn allows accumulation of TNFAIP3, a negative regulator of NF-kappa-B signaling, thereby providing feedback inhibition of BCR-induced NF-kappa-B activation. In T-cells, acts as a dual negative regulator of T-cell exhaustion and mitochondrial dysfunction. Promotes 'Lys-48'-linked polyubiquitination and proteasomal degradation of the transcription factor TOX, thereby attenuating the transition of progenitor exhausted T-cells towards terminal exhaustion. Also targets the mitochondrial phosphatase PGAM5 for degradation, thereby preventing excessive PGAM5-mediated dephosphorylation and activation of DRP1, which would otherwise drive pathological mitochondrial fission. Through these mechanisms, maintains mitochondrial fitness in T-cells during chronic antigen stimulation..

Function from UniProtKB (Q8WZ60), read 2026-09-23. CC BY 4.0.