The precise control of receptor levels is crucial for initiating cellular signaling transduction in response to specific ligands;however,such mechanisms regulating nodulation factor(NF)receptor(NFR)-mediated perceptio...The precise control of receptor levels is crucial for initiating cellular signaling transduction in response to specific ligands;however,such mechanisms regulating nodulation factor(NF)receptor(NFR)-mediated perception of NFs to establish symbiosis remain unclear.In this study,we unveil the pivotal role of the NFR-interacting RING-type E3 ligase 1(NIRE1)in regulating NFR1/NFR5 homeostasis to optimize rhizobial infection and nodule development in Lotus japonicus.We demonstrated that NiRE1 has a dual function in this regulatory process.It associates with both NFR1 and NFR5,facilitating their degradation through K48-linked polyubiquitination before rhizobial inoculation.However,following rhizobial inoculation,NFR1 phosphorylates NIRE1ata conserved residue,Tyr-109,inducing a functional switch in NIRE1,which enables NIRE1tomediateK63-linkedpolyubiquitination,thereby stabilizing NFR1/NFR5 in infected root cells.The introduction of phospho-dead NIRE1Y1osF leads to delayed nodule development,underscoring the significance of phosphorylation at Tyr-1o9 in orchestrating symbiotic processes.Conversely,expression of the phospho-mimic NIRE1Y0E results in the formation of spontaneous nodules in L.japonicus,further emphasizing the critical role of the phosphorylation-dependent functional switch in NiRE1.In summary,these findings uncover a fine-tuned symbiotic mechanism that a single E3 ligase could undergo a phosphorylationdependent functional switch to dynamically and precisely regulate NF receptor protein levels.展开更多
AIM: To evaluate the outcome of sub-centimeter-sized nodules (SCSNs) detected during surveillance for hepatocellular carcinoma (HCC) in patients at risk. METHODS: We retrospectively analyzed a total of 142 patients wi...AIM: To evaluate the outcome of sub-centimeter-sized nodules (SCSNs) detected during surveillance for hepatocellular carcinoma (HCC) in patients at risk. METHODS: We retrospectively analyzed a total of 142 patients with liver cirrhosis or chronic hepatitis B or C without a prior history of HCC in whom a SCSN was detected during HCC surveillance. We calculated the rate of HCC development from SCSNs in the study population and analyzed the differences in the baseline clinical characteristics and imaging features between the patients with SCSNs that eventually developed into HCC and patients with SCSNs that did not develop into HCC.RESULTS: During 667 person-years of follow-up, HCC developed in 33 patients. The calculated HCC development rate was 4.9% per year. The cumulative one-, two-, three- and five-year HCC development rates were 5.6%, 10.6%, 14.1% and 20.4%, respectively. Upon baseline comparison, the HCC group was older (54.4 ± 8.3 years vs 48.9 ± 9.4 years; P = 0.003) and had lower albumin levels (3.56 ± 0.58 g/dL vs 3.84 ± 0.55 g/dL; P = 0.012) and higher baseline alpha-fetoprotein (AFP) levels (8.5 ng/mL vs 5.4 ng/mL; P = 0.035) compared to the non-HCC group. Nodule pattern and initial radiologic diagnosis also differed between the two groups. Multivariate analysis revealed that age [P = 0.012, odds ratio (OR) =1.075, 95% confidence interval (CI) =1.016-1.137], sex (P = 0.009, OR = 3.969, 95% CI: 1.403-11.226), and baseline AFP level (P = 0.024, OR = 1.039, 95% CI: 1.005-1.073) were independent risk factors for developing HCC. CONCLUSION: The overall risk of HCC development in patients with SCSNs is similar to that in liver cirrhosis patients. Patients with these risk factors need to be closely monitored during follow-up.展开更多
基金the National Key R&D Program of China(2019YFA0904700)the National Natural Science Foundation of China(32200207 and 32090063)+1 种基金the China Postdoctoral Science Foundation(2019M662652)a Self-lnnovation grant from National Laboratory(AML2023B01).
文摘The precise control of receptor levels is crucial for initiating cellular signaling transduction in response to specific ligands;however,such mechanisms regulating nodulation factor(NF)receptor(NFR)-mediated perception of NFs to establish symbiosis remain unclear.In this study,we unveil the pivotal role of the NFR-interacting RING-type E3 ligase 1(NIRE1)in regulating NFR1/NFR5 homeostasis to optimize rhizobial infection and nodule development in Lotus japonicus.We demonstrated that NiRE1 has a dual function in this regulatory process.It associates with both NFR1 and NFR5,facilitating their degradation through K48-linked polyubiquitination before rhizobial inoculation.However,following rhizobial inoculation,NFR1 phosphorylates NIRE1ata conserved residue,Tyr-109,inducing a functional switch in NIRE1,which enables NIRE1tomediateK63-linkedpolyubiquitination,thereby stabilizing NFR1/NFR5 in infected root cells.The introduction of phospho-dead NIRE1Y1osF leads to delayed nodule development,underscoring the significance of phosphorylation at Tyr-1o9 in orchestrating symbiotic processes.Conversely,expression of the phospho-mimic NIRE1Y0E results in the formation of spontaneous nodules in L.japonicus,further emphasizing the critical role of the phosphorylation-dependent functional switch in NiRE1.In summary,these findings uncover a fine-tuned symbiotic mechanism that a single E3 ligase could undergo a phosphorylationdependent functional switch to dynamically and precisely regulate NF receptor protein levels.
文摘AIM: To evaluate the outcome of sub-centimeter-sized nodules (SCSNs) detected during surveillance for hepatocellular carcinoma (HCC) in patients at risk. METHODS: We retrospectively analyzed a total of 142 patients with liver cirrhosis or chronic hepatitis B or C without a prior history of HCC in whom a SCSN was detected during HCC surveillance. We calculated the rate of HCC development from SCSNs in the study population and analyzed the differences in the baseline clinical characteristics and imaging features between the patients with SCSNs that eventually developed into HCC and patients with SCSNs that did not develop into HCC.RESULTS: During 667 person-years of follow-up, HCC developed in 33 patients. The calculated HCC development rate was 4.9% per year. The cumulative one-, two-, three- and five-year HCC development rates were 5.6%, 10.6%, 14.1% and 20.4%, respectively. Upon baseline comparison, the HCC group was older (54.4 ± 8.3 years vs 48.9 ± 9.4 years; P = 0.003) and had lower albumin levels (3.56 ± 0.58 g/dL vs 3.84 ± 0.55 g/dL; P = 0.012) and higher baseline alpha-fetoprotein (AFP) levels (8.5 ng/mL vs 5.4 ng/mL; P = 0.035) compared to the non-HCC group. Nodule pattern and initial radiologic diagnosis also differed between the two groups. Multivariate analysis revealed that age [P = 0.012, odds ratio (OR) =1.075, 95% confidence interval (CI) =1.016-1.137], sex (P = 0.009, OR = 3.969, 95% CI: 1.403-11.226), and baseline AFP level (P = 0.024, OR = 1.039, 95% CI: 1.005-1.073) were independent risk factors for developing HCC. CONCLUSION: The overall risk of HCC development in patients with SCSNs is similar to that in liver cirrhosis patients. Patients with these risk factors need to be closely monitored during follow-up.
