The PAXT connection is a modifier of rare codon-enriched protein expression

Abstract Synonymous codons occur at unequal rates in the coding genome, with those represented least often termed ‘rare.’ Rare codon-enriched genes typically exhibit poor expression due to reduced transcription, mRNA stability, export, and translation. However, there are an increasing number of examples whereby rare codon-enriched genes are paradoxically highly expressed, suggestive of mechanisms to overcome the poor expression imposed by rare codons. To identify codon-dependent modifiers, we screen a targeted sgRNA library for genes that, when inactivated, increase the expression of rare versus common codon-enriched fluorescent reporters. This identifies the PAXT connection, a nuclear complex that targets transcripts to the exosome for degradation. Targeted loss of a PAXT component leads to a small but preferential increase in mRNA levels and stability and a more pronounced increase in protein expression of rare compared to common codon-enriched reporters. Transcriptomics coupled to proteomics further reveals that this leads to a preferential increase in the expression of endogenous proteins encoded by poorly expressed and long mRNAs specifically enriched in rare codons. Thus, we identify the PAXT connection as a genetic suppressor of poorly expressed genes enriched in rare codons.