The intracellular domain of ß-dystroglycan mediates the nucleolar stress response by suppressing UBF transcriptional activity.

ß-dystroglycan (ß-DG) is a key component of multiprotein complexes in the plasma membrane and nuclear envelope. In addition, ß-DG undergoes two successive proteolytic cleavages that result in the liberation of its intracellular domain (ICD) into the cytosol and nucleus. However, stimuli-inducing ICD cleavage and the physiological relevance of this proteolytic fragment are largely unknown. In this study we show for the first time that ß-DG ICD is targeted to the nucleolus where it interacts with the nuclear proteins B23 and UBF (central factor of Pol I-mediated rRNA gene transcription) and binds to rDNA promoter regions. Interestingly DG silencing results in reduced B23 and UBF levels and aberrant nucleolar morphology. Furthermore, ß-DG ICD cleavage is induced by different nucleolar stressors, including oxidative stress, acidosis, and UV irradiation, which implies its participation in the response to nucleolar stress. Consistent with this idea, overexpression of ß-DG elicited mislocalization and decreased levels of UBF and suppression of rRNA expression, which in turn provoked altered ribosome profiling and decreased cell growth. Collectively our data reveal that ß-DG ICD acts as negative regulator of rDNA transcription by impeding the transcriptional activity of UBF, as a part of the protective mechanism activated in response to nucleolar stress.

Publisher Correction: Retrograde trafficking of ß-dystroglycan from the plasma membrane to the nucleus.

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Retrograde trafficking of ß-dystroglycan from the plasma membrane to the nucleus.

ß-Dystroglycan (ß-DG) is a transmembrane protein with critical roles in cell adhesion, cytoskeleton remodeling and nuclear architecture. This functional diversity is attributed to the ability of ß-DG to target to, and conform specific protein assemblies at the plasma membrane (PM) and nuclear envelope (NE). Although a classical NLS and importin α/ß mediated nuclear import pathway has already been described for ß-DG, the intracellular trafficking route by which ß-DG reaches the nucleus is unknown. In this study, we demonstrated that ß-DG undergoes retrograde intracellular trafficking from the PM to the nucleus via the endosome-ER network. Furthermore, we provided evidence indicating that the translocon complex Sec61 mediates the release of ß-DG from the ER membrane, making it accessible for importins and nuclear import. Finally, we show that phosphorylation of ß-DG at Tyr890 is a key stimulus for ß-DG nuclear translocation. Collectively our data describe the retrograde intracellular trafficking route that ß-DG follows from PM to the nucleus. This dual role for a cell adhesion receptor permits the cell to functionally connect the PM with the nucleus and represents to our knowledge the first example of a cell adhesion receptor exhibiting retrograde nuclear trafficking and having dual roles in PM and NE.

[Hypertriglyceridemia and low HDL cholesterol as high impact factors for metabolic syndrome diagnosis in apparently healthy adults]. / Hipertrigliceridemia e hipoalfalipoproteinemia. Su impacto para diagnosticar síndrome metabólico.

OBJECTIVE: to determine the impact of lipid serum abnormalities and the prevalence of metabolic syndrome (MS) in healthy adults. METHODS: a cross-sectional, prospective and observational study in apparently healthy adults aged 20 to 60 years who had at least three of the following criteria: abdominal obesity (waist circumference > 102 cm in men and > 88 cm in women), triglycerides ≥ 150 mg/dL, HDL cholesterol < 40 mg/dL in men and < 50 mg/dL in women, blood pressure ≥ 130/85 mmHg and fasting glucose ≥ 110 mg/dL). RESULTS: the prevalence of MS was 20 %, being higher in women (67.7 %) than men (32.3 %). However, no dependence was found with gender (χ(2)= 2.059, p = 0.151). The age range with a higher prevalence of was 45-49 years. Low HDL cholesterol [HR = 11,059 (3.559, 34.610) p < 0.01], was present in 67.9 % of women and hypertriglyceridemia [HR = 15.53 (4.975, 48.513) p < 0.01] was present in 60.5 % of men. CONCLUSIONS: the results suggested that hypertriglyceridemia and hypoalphalipoproteinemia are high impact factors for MS in adults.