Membrane protein folding is an error-prone process that is subject to numerous forms of biochemical regulation. The ribosome and its ensemble of accessory proteins employ a variety of mechanisms to monitor membrane protein folding and misfolding during translation that are essential for the maintenance of protein homeostasis. Nevertheless, it’s unclear how this biosynthetic machinery detects and responds to folding and misfolding in real time. We recently found that the mechanical forces generated by the translocon-mediated membrane integration of transmembrane domains can stimulate a translational recoding event known as -1 programmed ribosomal frameshifting (-1PRF). Alphaviruses modulate the efficiency of -1PRF through crosstalk between an mRNA structure that pauses the ribosome on a slippery-sequence of the transcript during the translocon-mediated cotranslational folding. Based on the features of this motif, we searched the human transcriptome for other potential sites that may promote this cotranslational feedback and identified hundred potential candidates. Preliminary efforts to validate certain hits have identified active -1PRF motifs within several human membrane proteins. Ribosomal frameshifting at these sites results in the premature termination of translation. These findings suggest a novel role for ribosomal frameshifting in eukaryotic protein homeostasis.

Modulation of ribosomal frameshifting by cotranslational folding and misfolding of the nascent polypeptide chain

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