TY - JOUR
T1 - The intracellular domain of β-dystroglycan mediates the nucleolar stress response by suppressing UBF transcriptional activity
AU - Azuara-Medina, Paulina Margarita
AU - Sandoval-Duarte, Ariana María
AU - Morales-Lázaro, Sara L.
AU - Modragón-González, Ricardo
AU - Vélez-Aguilera, Griselda
AU - Gómez-López, Juan de Dios
AU - Jiménez-Gutiérrez, Guadalupe Elizabeth
AU - Tiburcio-Félix, Reynaldo
AU - Martínez-Vieyra, Ivette
AU - Suárez-Sánchez, Rocío
AU - Längst, Gernot
AU - Magaña, Jonathan Javier
AU - Winder, Steve J.
AU - Ortega, Arturo
AU - Ramos Perlingeiro, Rita de Cassia
AU - Jacobs, Laura A.
AU - Cisneros, Bulmaro
N1 - 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.
Publisher Copyright:
© 2019, The Author(s).
PY - 2019/3/1
Y1 - 2019/3/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41419-019-1454-z
DO - 10.1038/s41419-019-1454-z
M3 - Article
C2 - 30814495
AN - SCOPUS:85062260144
SN - 2041-4889
VL - 10
JO - Cell Death and Disease
JF - Cell Death and Disease
IS - 3
M1 - 196
ER -