The formin protein Diaph3 is an actin nucleator that regulates numerous cytoskeleton-dependent cellular processes through the activation of actin polymerization. Expression and activity of Diaph3 is tightly regulated: lack of Diaph3 results in developmental defects and embryonic lethality in mice, while overexpression of Diaph3 causes auditory neuropathy. It is known that Diaph3 homophilic interactions include the intramolecular interaction of its Dia-inhibitory domain (DID)-diaphanous autoregulatory domain (DAD) domains and the intermolecular interactions of DD-DD domains or FH2-FH2 domains. However, the physiological significance of these interactions in Diaph3 protein stability and activity is not fully understood. In this study, we show that FH2-FH2 interaction promotes Diaph3 activity, while DID-DAD and DD-DD interactions inhibit Diaph3 activity through distinct mechanisms. DID-DAD interaction is responsible for the autoinhibition of Diaph3 protein, which is disrupted by binding of Rho GTPases. Interestingly, we find that DID-DAD interaction stabilizes the expression of each DID or DAD domain against proteasomal-mediated degradation. Disruption of DID-DAD interaction by RhoA binding or M1041A mutation causes increased Diaph3 activity and accelerated degradation of the activated Diaph3 protein. Further, the activated Diaph3 is ubiquitinated at K1142/1143/1144 lysine residues by the E3 ligase Stub1. Expression of Stub1 is causally related to the stability and activity of Diaph3. Knockdown of Stub1 in mouse cochlea results in hair cell stereocilia defects, neuronal degeneration, and hearing loss, resembling the phenotypes of mice overexpressing Diaph3. Thus, our study reports a novel regulatory mechanism of Diaph3 protein expression and activity whereby the active but not inactive Diaph3 is readily degraded to prevent excessive actin polymerization.
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http://dx.doi.org/10.1016/j.jbc.2024.107813 | DOI Listing |
Int J Mol Sci
November 2024
Institute of Animal Husbandry and Veterinary Research, Hainan Academy of Agricultural Sciences, Key Laboratory of Tropical Animal Breeding and Epidemic Disease Research, Haikou 571100, China.
Copy number variation (CNV) serves as a crucial source of genomic variation and significantly aids in the mining of genomic information in cattle. This study aims to analyze re-sequencing data from Chinese Hainan yellow cattle, to uncover breed CNV information, and to elucidate the resources of population genetic variation. We conducted whole-genome sequencing on 30 Chinese Hainan yellow cattle, thus generating 814.
View Article and Find Full Text PDFInt J Genomics
October 2024
Livestock Genetics, International Livestock Research Institute (ILRI), Addis Ababa, Ethiopia.
Identifying genetic regions and candidate genes that influence milk production traits is critical for understanding genetic inheritance and improving both the quality and quantity of milk in dairy cattle. Crossbred dairy cattle significantly contribute to increasing milk production and ensuring food security in the middle- and high-altitude regions of Ethiopia. However, the genetic architecture underlying their milk yield and composition traits has not yet been thoroughly investigated.
View Article and Find Full Text PDFFront Immunol
October 2024
MOE Key Laboratory for Cellular Dynamics and Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China.
The term "Long-COVID" (LC) is characterized by the aftereffects of COVID-19 infection. Various studies have suggested that Epstein-Barr virus (EBV) reactivation is among the significant reported causes of LC. However, there is a lack of in-depth research that could largely explore the pathogenic mechanism and pinpoint the key genes in the EBV and LC context.
View Article and Find Full Text PDFEndokrynol Pol
October 2024
Department of Otorhinolaryngology; Hebei Medical University Fourth Affiliated Hospital and Hebei Provincial Tumour Hospital, Shijiazhuang, Hebei, China.
Front Biosci (Landmark Ed)
September 2024
Department of Urology, Qingdao Hospital, University of Health and Rehabilitation Sciences (Qingdao Municipal Hospital), 266071 Qingdao, Shandong, China.
Background: Cathepsin C (CTSC) participates in the development of numerous cancers; however, its function in bladder cancer (BCa) remains largely unknown.
Methods: Bioinformatics prediction, quantitative reverse transcription polymerase chain reaction (RT-qPCR) assay, and Western blot assay were used to determine CTSC expression in BCa tissues, paracancer tissues, BCa cells, and normal uroepithelial cells (SV-HUC-1). Colony formation, cell counting kit-8 (CCK-8), and Transwell assays were utilised to ascertain the involvement of CTSC in BCa.
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