Proteomics

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LENG8 mediates nuclear retention and degradation of misprocessed mRNAs and noncoding RNAs

ABSTRACT: Incompletely processed and misprocessed mRNAs as well as numerous noncoding RNAs are retained in the nucleus and often degraded, and defects in this quality control mechanism have been linked to various diseases, including cancer and neurodegeneration. However, the underlying mechanisms remain poorly understood. Here we show that LENG8 is recruited to pre-mRNAs by splicing factors, including the U1 snRNP. Once RNA-bound, LENG8 is both necessary and sufficient to sequester RNA in the nucleus. LENG8 depletion leads to the leakage of misprocessed mRNAs, including intronically polyadenylated and intron-retained mRNAs, as well as noncoding RNAs into the cytoplasm. Mechanistically, we showed that LENG8 binds to PCID2 and SEM1 to form an evolutionarily conserved complex, referred to as REX (repressor of export), and causes RNA nuclear retention by acting as a dominant negative factor for the essential mRNA export factor TREX2. Finally, LENG8 promotes RNA degradation by recruiting the ZFC3H1-MTR4-exosome complex. Thus, LENG8 is a key quality control factor that keeps pre-mRNAs in the nucleus until they are fully and correctly processed.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Clinton Yu  

LAB HEAD: Yongsheng Shi

PROVIDER: PXD065356 | Pride | 2026-03-30

REPOSITORIES: Pride

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Publications

LENG8 mediates RNA nuclear retention and degradation in eukaryotes.

Tian Lusong L   Liu Liang L   Yoon Yoseop Y   Soles Lindsey V LV   Valdez Marielle M   Jeong Joshua J   Yu Clinton C   Huang Lan L   Shi Yongsheng Y  

Molecular cell 20260319 8

In eukaryotes, incompletely and aberrantly processed mRNAs as well as numerous noncoding RNAs are retained in the nucleus and often degraded, but the underlying quality-control mechanisms remain poorly defined. Here, we identify LENG8 as a conserved RNA nuclear retention and degradation factor. LENG8 is recruited to pre-mRNAs by splicing factors, including the U1 small nuclear ribonucleoprotein particle (snRNP). It associates with PCID2 and SEM1 to form the REX (repressor of export) complex, whi  ...[more]

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