TY - JOUR
T1 - The Perlman syndrome DIS3L2 exoribonuclease safeguards endoplasmic reticulum-targeted mRNA translation and calcium ion homeostasis
AU - Pirouz, Mehdi
AU - Wang, Chih Hao
AU - Liu, Qi
AU - Ebrahimi, Aref G.
AU - Shamsi, Farnaz
AU - Tseng, Yu Hua
AU - Gregory, Richard I.
N1 - Funding Information:
This work was supported by grants from the US National Institute of General Medical Sciences (NIH-NIGMS) (R01GM086386) to R.I.G, the National Institute of Diabetes and Digestive and Kidney Diseases (NIH-NIDDK) (K01DK121861) to M.P. and a fellowship from the Manton Center for Orphan Disease Research to M.P. We thank Dr. R. Nish-inakamura from Kumamoto University, Japan, for generous sharing of the Osr1-GFP reporter mouse ESC line.
Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12/1
Y1 - 2020/12/1
N2 - DIS3L2-mediated decay (DMD) is a surveillance pathway for certain non-coding RNAs (ncRNAs) including ribosomal RNAs (rRNAs), transfer RNAs (tRNAs), small nuclear RNAs (snRNAs), and RMRP. While mutations in DIS3L2 are associated with Perlman syndrome, the biological significance of impaired DMD is obscure and pathological RNAs have not been identified. Here, by ribosome profiling (Ribo-seq) we find specific dysregulation of endoplasmic reticulum (ER)-targeted mRNA translation in DIS3L2-deficient cells. Mechanistically, DMD functions in the quality control of the 7SL ncRNA component of the signal recognition particle (SRP) required for ER-targeted translation. Upon DIS3L2 loss, sustained 3’-end uridylation of aberrant 7SL RNA impacts ER-targeted translation and causes ER calcium leakage. Consequently, elevated intracellular calcium in DIS3L2-deficient cells activates calcium signaling response genes and perturbs ESC differentiation. Thus, DMD is required to safeguard ER-targeted mRNA translation, intracellular calcium homeostasis, and stem cell differentiation.
AB - DIS3L2-mediated decay (DMD) is a surveillance pathway for certain non-coding RNAs (ncRNAs) including ribosomal RNAs (rRNAs), transfer RNAs (tRNAs), small nuclear RNAs (snRNAs), and RMRP. While mutations in DIS3L2 are associated with Perlman syndrome, the biological significance of impaired DMD is obscure and pathological RNAs have not been identified. Here, by ribosome profiling (Ribo-seq) we find specific dysregulation of endoplasmic reticulum (ER)-targeted mRNA translation in DIS3L2-deficient cells. Mechanistically, DMD functions in the quality control of the 7SL ncRNA component of the signal recognition particle (SRP) required for ER-targeted translation. Upon DIS3L2 loss, sustained 3’-end uridylation of aberrant 7SL RNA impacts ER-targeted translation and causes ER calcium leakage. Consequently, elevated intracellular calcium in DIS3L2-deficient cells activates calcium signaling response genes and perturbs ESC differentiation. Thus, DMD is required to safeguard ER-targeted mRNA translation, intracellular calcium homeostasis, and stem cell differentiation.
UR - http://www.scopus.com/inward/record.url?scp=85085303189&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85085303189&partnerID=8YFLogxK
U2 - 10.1038/s41467-020-16418-y
DO - 10.1038/s41467-020-16418-y
M3 - Article
C2 - 32457326
AN - SCOPUS:85085303189
SN - 2041-1723
VL - 11
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 2619
ER -