Details

Autor(en) / Beteiligte

• Nguyen, Tuan M
• Kabotyanski, Elena B
• Reineke, Lucas C
• Shao, Jiaofang
• Xiong, Feng
• Lee, Joo-Hyung
• Dubrulle, Julien
• Johnson, Hannah
• Stossi, Fabio
• Tsoi, Phoebe S
• Choi, Kyoung-Jae
• Ellis, Alexander G
• Zhao, Na
• Cao, Jin
• Adewunmi, Oluwatoyosi
• Ferreon, Josephine C
• Ferreon, Allan Chris M
• Neilson, Joel R
• Mancini, Michael A
• Chen, Xi
• Kim, Jongchan
• Ma, Li
• Li, Wenbo
• Rosen, Jeffrey M

Titel

The SINEB1 element in the long non-coding RNA Malat1 is necessary for TDP-43 proteostasis

Ist Teil von

• Nucleic acids research, 2020-03, Vol.48 (5), p.2621-2642

Ort / Verlag

England

Erscheinungsjahr

2020

Quelle

MEDLINE

Beschreibungen/Notizen

• Transposable elements (TEs) comprise a large proportion of long non-coding RNAs (lncRNAs). Here, we employed CRISPR to delete a short interspersed nuclear element (SINE) in Malat1, a cancer-associated lncRNA, to investigate its significance in cellular physiology. We show that Malat1 with a SINE deletion forms diffuse nuclear speckles and is frequently translocated to the cytoplasm. SINE-deleted cells exhibit an activated unfolded protein response and PKR and markedly increased DNA damage and apoptosis caused by dysregulation of TDP-43 localization and formation of cytotoxic inclusions. TDP-43 binds stronger to Malat1 without the SINE and is likely 'hijacked' by cytoplasmic Malat1 to the cytoplasm, resulting in the depletion of nuclear TDP-43 and redistribution of TDP-43 binding to repetitive element transcripts and mRNAs encoding mitotic and nuclear-cytoplasmic regulators. The SINE promotes Malat1 nuclear retention by facilitating Malat1 binding to HNRNPK, a protein that drives RNA nuclear retention, potentially through direct interactions of the SINE with KHDRBS1 and TRA2A, which bind to HNRNPK. Losing these RNA-protein interactions due to the SINE deletion likely creates more available TDP-43 binding sites on Malat1 and subsequent TDP-43 aggregation. These results highlight the significance of lncRNA TEs in TDP-43 proteostasis with potential implications in both cancer and neurodegenerative diseases.