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

Paulina Margarita Azuara-Medina, Ariana María Sandoval-Duarte, Sara L. Morales-Lázaro, Ricardo Modragón-González, Griselda Vélez-Aguilera, Juan de Dios Gómez-López, Guadalupe Elizabeth Jiménez-Gutiérrez, Reynaldo Tiburcio-Félix, Ivette Martínez-Vieyra, Rocío Suárez-Sánchez, Gernot Längst, Jonathan Javier Magaña, Steve J. Winder, Arturo Ortega, Rita de Cassia Ramos Perlingeiro, Laura A. Jacobs, Bulmaro Cisneros

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Abstract

β-dystroglycan (β-DG) is a key component of multiprotein complexes in the plasma membrane and nuclear envelope. In addition, β-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 β-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, β-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 β-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 β-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.

Original languageEnglish (US)
Article number196
JournalCell Death and Disease
Volume10
Issue number3
DOIs
StatePublished - Mar 1 2019

Bibliographical note

Funding Information:
This work was funded by CONACYT Mexico, a grant to BC (237123) and MRC PhD studentship to LAJ (G1000405-1/1 MR//J500513/1.

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