Coenzyme A (CoA) is an essential metabolic cofactor whose biosynthesis is controlled by pantothenate kinases (PANKs), the rate-limiting enzymes in CoA synthesis. Although CoA production is extensively regulated, whether PANK abundance is controlled by selective protein degradation remains unknown. Here, we identify PANK1{beta} and PANK3 as substrates of the Arg/N-degron pathway. Two mechanistically distinct E3 ligase systems, UBR4-KCMF1 and MKLN1-CTLH, independently converge on a common N-terminal MK Arg/N-degron to promote PANK degradation and restrict CoA biosynthesis. UBR4-KCMF1 recognizes the MK Arg/N-degron through KCMF1 ZZ domain, whereas CTLH complex employs the B30.2-domain proteins RanBP9 and RanBP10 as previously unrecognized Arg/N-degron recognins. Structural, biochemical, and cellular analyses demonstrate that RanBP9 and RanBP10 recognize both Met-X and canonical Arg/N-degrons through their B30.2 domains, using a mechanism distinct from canonical UBR proteins. Together, these findings establish a new branch of the mammalian Arg/N-degron pathway and reveal ubiquitin-dependent control of PANK abundance in CoA homeostasis.
Wang, X., Wang, B., Zhang, L., Yan, S., Zhao, N., Zhao, Y., Shi, F., Yin, S., Chen, D., Yu, Y., Dong, C., Mi, W.
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