The MTR4/hnRNPK complex surveils aberrant polyadenylated RNAs with multiple exons

Area of Science:

• Molecular Biology
• RNA Biology
• Cellular Mechanisms

Background:

• Cellular RNA surveillance pathways degrade aberrant RNAs arising from transcription and processing errors.
• The RNA exosome complex, aided by factors like MTR4, plays a crucial role in degrading these defective RNAs.
• Aberrant RNA species can arise from various defects, including transcriptional read-through.

Purpose of the Study:

• To identify and characterize aberrant RNAs in cells lacking the MTR4 protein.
• To elucidate the role of MTR4 in the degradation of specific aberrant RNA species.
• To investigate the cellular consequences of accumulating aberrant RNAs and their translated products.

Main Methods:

• Long-read direct RNA sequencing
• 3' end sequencing
• Depletion of MTR4 protein in human cells
• Immunoprecipitation assays
• Analysis of protein condensate formation

Main Results:

• MTR4 destabilizes intronic polyadenylated transcripts generated by transcriptional read-through, termed 3' eXtended Transcripts (3XTs).
• MTR4 collaborates with hnRNPK to recognize and degrade 3XTs containing multiple exons.
• An aberrant protein translated from a KCTD13 3XT forms aberrant protein condensates (KeXT bodies), targeted by the hnRNPK-MTR4-RNA exosome pathway.

Conclusions:

• The hnRNPK-MTR4-RNA exosome pathway actively degrades 3XTs, preventing the formation of aberrant protein condensates.
• RNA surveillance mechanisms are critical for inhibiting the accumulation of defective proteins derived from aberrant transcripts.
• This study reveals a novel mechanism by which cells control potentially toxic protein aggregates originating from faulty RNA species.