Parallel Arg/N-degron recognition systems regulate coenzyme A biosynthesis

Authors

Wang, X., Wang, B., Zhang, L., Yan, S., Zhao, N., Zhao, Y., Shi, F., Yin, S., Chen, D., Yu, Y., Dong, C., Mi, W.

Abstract

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.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 18 Sep 2026.

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