Activation of RhoC by regulatory ubiquitination is mediated by LNX1 and suppressed by LIS1.

TitleActivation of RhoC by regulatory ubiquitination is mediated by LNX1 and suppressed by LIS1.
Publication TypeJournal Article
Year of Publication2022
AuthorsKholmanskikh S, Singh S, M Ross E
JournalSci Rep
Date Published2022 Oct 03
KeywordsAnimals, Humans, rho GTP-Binding Proteins, rho-Specific Guanine Nucleotide Dissociation Inhibitors, rhoA GTP-Binding Protein, rhoC GTP-Binding Protein, Ubiquitin-Protein Ligases, Ubiquitination

Regulation of Rho GTPases remains a topic of active investigation as they are essential participants in cell biology and the pathophysiology of many human diseases. Non-degrading ubiquitination (NDU) is a critical regulator of the Ras superfamily, but its relevance to Rho proteins remains unknown. We show that RhoC, but not RhoA, is a target of NDU by E3 ubiquitin ligase, LNX1. Furthermore, LNX1 ubiquitination of RhoC is negatively regulated by LIS1 (aka, PAFAH1B1). Despite multiple reports of functional interaction between LIS1 and activity of Rho proteins, a robust mechanism linking the two has been lacking. Here, LIS1 inhibition of LNX1 effects on RhoGDI-RhoC interaction provides a molecular mechanism underpinning the enhanced activity of Rho proteins observed upon reduction in LIS1 protein levels. Since LNX1 and RhoC are only found in vertebrates, the LIS1-LNX1-RhoC module represents an evolutionarily acquired function of the highly conserved LIS1. While these nearly identical proteins have several distinct RhoA and RhoC downstream effectors, our data provide a rare example of Rho-isoform specific, upstream regulation that opens new therapeutic opportunities.

Alternate JournalSci Rep
PubMed ID36192543
PubMed Central IDPMC9529947
Grant ListR01NS105477 / NH / NIH HHS / United States
R01 NS102904 / NS / NINDS NIH HHS / United States