TAX1BP1 and FIP200 orchestrate non-canonical autophagy of p62 aggregates for mouse neural stem cell maintenance.

Autophagy plays a pivotal role in diverse biological processes, including the maintenance and differentiation of neural stem cells (NSCs). Interestingly, while complete deletion of Fip200 severely impairs NSC maintenance and differentiation, inhibiting canonical autophagy via deletion of core genes, such as Atg5, Atg16l1, and Atg7, or blockade of canonical interactions between FIP200 and ATG13 (designated as FIP200-4A mutant or FIP200 KI) does not produce comparable detrimental effects. This highlights the likely critical involvement of the non-canonical functions of FIP200, the mechanisms of which have remained elusive. Here, utilizing genetic mouse models, we demonstrated that FIP200 mediates non-canonical autophagic degradation of p62/sequestome1, primarily via TAX1BP1 in NSCs. Conditional deletion of Tax1bp1 in fip200 hGFAP conditional knock-in (cKI) mice led to NSC deficiency, resembling the fip200 hGFAP conditional knockout (cKO) mouse phenotype. Notably, reintroducing wild-type TAX1BP1 not only restored the maintenance of NSCs derived from tax1bp1-knockout fip200 hGFAP cKI mice but also led to a marked reduction in p62 aggregate accumulation. Conversely, a TAX1BP1 mutant incapable of binding to FIP200 or NBR1/p62 failed to achieve this restoration. Furthermore, conditional deletion of Tax1bp1 in fip200 hGFAP cKO mice exacerbated NSC deficiency and p62 aggregate accumulation compared to fip200 hGFAP cKO mice. Collectively, these findings illustrate the essential role of the FIP200-TAX1BP1 axis in mediating the non-canonical autophagic degradation of p62 aggregates towards NSC maintenance and function, presenting novel therapeutic targets for neurodegenerative diseases.

The CXCR4 might be a potential biomarker for esophageal squamous cell carcinoma: A meta-analysis.

OBJECTIVE: To evaluate the relationship between CXCL12/CXCR4 and the progress, prognosis of esophageal squamous cell carcinoma (ESCC), providing evidence for potential early diagnosis, clinical treatment, prognosis evaluation, and therapeutic target of ESCC. METHODS: Databases of PubMed, the Cochrane Library, Embase, and Web of Science were searched for the relationship between CXCL12/CXCR4 and clinicopathological characteristics and survival time of ESCC. Stata16.0 software was used to conduct meta-analysis. RESULTS: A total of 10 studies involving 1216 cases of patients with ESCC were included in our study. The results indicated that high-level expression of CXCR4 was significantly correlated with tumor differentiation [OR = 0.69, 95% confidence interval (CI): (0.50, 0.97)], tumor infiltration [OR = 0.39, 95% CI: (0.25, 0.61)], lymph node metastasis [OR = 0.36, 95% CI: (0.21, 0.61)], clinical stage [OR = 0.33, 95% CI: (0.24, 0.45)] of ESCC. The expression of CXCR4 was also significantly correlated with OS [HR = 2.00, 95% CI: (1.63, 2.45)] and disease-free survival [HR = 1.76, 95% CI: (1.44, 2.15)] in patients of ESCC after surgical resection. No significant relationship was observed between the expression of CXCL12 and the clinicopathological characteristics of ESCC. CONCLUSION: CXCR4 might be a potential biomarker for the progress and prognosis evaluation, and therapeutic target for ESCC.

[Distribution Laws of PCOS Syndrome Types and Features of Sex Hormone Levels and Glucose Metabolism].

OBJECTIVE: To analyze distribution laws of polycystic ovary syndrome PCOS) syndrome types and features of sex hormone levels and glucose metabolism, providing evidence for clinical syndrome typing, diagnosis and treatment. METHODS: Totally 237 PCOS patient were recruited. Their basic information and clinical data were collected and syndrome typed as Shen yin deficiency type, Shen yang deficiency type, Gan depression type, phlegm dampness type, blood stasis type. Data were analyzed by using SPSS21. 0 Software package. Basic features, hormone levels, and glucose metabolism were observed in patients with different syndrome types. RESULTS: (1) The laws of syndrome distribution: Shen yin deficiency type in 46 cases (19. 41%), Shen yang deficiency type in 61 cases (25. 74%), Gan depression type in 48 cases (20. 25%), phlegm dampness type in 46 cases (19. 41%), blood stasis type in 36 cases (15.19%). (2) The levels of sex hormones: Compared with patients with Shen yin deficiency type, luteinizing hormone (LH) was higher in patients with Shen yang deficiency type (P <0. 01 , P <0. 05) ; LH was lower in patients with Gan depression type and phlegm dampness type (P <0. 01 , P <0. 05) ; follicle stimulating hormone (FSH) was lower in patients with phlegm dampness type (P <0.05); LH/FSH ratio was higher in patients with Shen yang deficiency type (P <0. 01); testosterone (T) level was lower in patients with Gan depression type and blood stasis type (P <0. 05, P <0. 01) ; prolactin (PRL) level was higher in patients with blood stasis type and phlegm dampness type (P <0. 05, P <0. 01). Compared with patients with Shen yang deficiency type, LH level and LH/FSH ratio were lower in patients with Gan depression type, phlegm dampness type, and blood stasis type (P <0. 01) ; FSH was lower in patients with phlegm dampness type (P<0.05); T was also lower in patients with Gan depression type and blood stasis type (P <0.05, P < 0.01); PRL was higher in patients with Gan depression type and phlegm dampness type (P <0.01, P < 0. 05). Compared with patients with Gan depression type, PRL was lower in patients with phlegm dampness type and blood stasis type (P <0. 01). Ddehydroepiandrosterone sulfate (DHEAS) level was the lowest in patients with blood stasis type (P <0. 05, P <0. 01). There was no statistical difference in estradiol (E2) among all groups (P>0.05). (3) The characteristics of glucose metabolism: Compared with patients with phlegm dampness type, fasting insulin (FINS), 2 h insulin (INS 2 h) , 3 h insulin (INS 3 h) , insulin/glucose (I/G), homeostatic model for insulin resistance (HOMA-IR) were lower in patients with Shen yin deficiency type, Shen yang deficiency type, Gan depression type, blood stasis type (P <0. 01) ; islet ß-cell function index (HOMA-ß) was lower in patients with Shen yang deficiency type, Gan depression type, blood stasis type (all P <0. 01); 2 h glucose (GLU 2 h) was lower in patients with Shen yin deficiency type, Shen yang deficiency type, blood stasis type (P <0. 05, P <0. 01); 3 h glucose (GLU 3 h) was lower in patients with Shen yin deficiency type (P <0. 05). Compared with patients with Gan depression type, INS 2 h and GLU 2 h were also lower patients with Shen yin deficiency type (P <0. 05, P <0. 01). CONCLUSIONS: There exists certain distribution laws of syndrome types in PCOS patients. Besides, different syndrome types had certain relevance with sex hormone and glucose metabolism features.

Mitochondrial ubiquitin ligase MARCH5 promotes TLR7 signaling by attenuating TANK action.

The signaling of Toll-like receptors (TLRs) is the host's first line of defense against microbial invasion. The mitochondrion is emerging as a critical platform for antiviral signal transduction. The regulatory role of mitochondria for TLR signaling remains to be explored. Here, we show that the mitochondrial outer-membrane protein MARCH5 positively regulates TLR7 signaling. Ectopic expression or knockdown of MARCH5 enhances or impairs NF-κB-mediated gene expression, respectively. MARCH5 interacts specifically with TANK, and this interaction is enhanced by R837 stimulation. MARCH5 catalyzes the K63-linked poly-ubiquitination of TANK on its Lysines 229, 233, 280, 302 and 306, thus impairing the ability of TANK to inhibit TRAF6. Mislocalization of MARCH5 abolishes its action on TANK, revealing the critical role of mitochondria in modulating innate immunity. Arguably, this represents the first study linking mitochondria to TLR signaling.