hnRNPL and nucleolin bind LINE-1 RNA and function as host factors to modulate retrotransposition

Abstract

Long INterspersed Element one (LINE-1, or L1), is a widely distributed, autonomous retrotransposon in mammalian genomes. During retrotransposition, L1 RNA functions first as a dicistronic mRNA and then as a template for cDNA synthesis. Previously, we defined internal ribosome entry sequences (IRESs) upstream of both ORFs (ORF1 and ORF2) in the dicistronic mRNA encoded by mouse L1. Here, RNA affinity chromatography was used to isolate cellular proteins that bind these regions of L1 RNA. Four proteins, the heterogeneous nuclear ribonucleoproteins (hnRNPs) R, Q and L, and nucleolin (NCL), appeared to interact specifically with the ORF2 IRES. These were depleted from HeLa cells to examine their effects on L1 IRES-mediated translation and L1 retrotransposition. NCL knockdown specifically reduced the ORF2 IRES activity, L1 and L1-assisted Alu retrotransposition without altering L1 RNA or protein abundance. These findings are consistent with NCL acting as an IRES trans-acting factor (ITAF) for ORF2 translation and hence a positive host factor for L1 retrotransposition. In contrast, hnRNPL knockdown dramatically increased L1 retrotransposition as well as L1 RNA and ORF1 protein, indicating that this cellular protein normally interferes with retrotransposition. Thus, hnRNPL joins a small, but growing list of cellular proteins that are potent negative regulators of L1 retrotransposition.

Massive horizontal transfer of transposable elements in insects

“…Instead, as proposed for HGT and HTT in bacteria (1,25,26), compatibility between TEs and recipient host cells may decrease as genetic distance from source lineages increases. Transposition is known to involve a number of interactions between TEs and host cellular factors (e.g., transcription factors and chromatin), which, depending on the type of TE, may be limited or very intricate (27)(28)(29)(30). For example, some DNA transposons from the Tc1-Mariner superfamily only require their transposase to transpose in vitro (27).…”

Decoding the noncoding: Prospective of lncRNA-mediated innate immune regulation

“…THRIL was found to regulate basal transcription and induction of TNFa expression by interacting with hnRNP-L. HnRNP-L is located in both the nucleus and cytoplasm. In the nucleus, hnRNP-L binds to and regulates the activities of Line-1 retrotransposon 38 ; in the cytoplasm, it binds to and stabilizes target mRNAs response to stress stimuli. 39 Our work revealed a novel role for the THRIL-hnRNP-L RNP complex as a transcriptional activator at the TNFa promoter.…”

The long noncoding RNA THRIL regulates TNFα expression through its interaction with hnRNPL

“…Recent studies indicate that hnRNPL is involved in the mammalian stress response and plays dual roles in the nucleus and cytoplasm (18,19). In the nucleus, hnRNPL binds L1 retrotransposon RNAs and helps to silence endogenous retrotransposon expression (19) whereas, in the cytoplasm, hnRNPL is involved in a stress-responsive switch that controls VEGFA expression (18).…”