# Sec61β maintains cytoplasmic proteostasis via ARIH1-mediated translational repression upon ER stress

## TL;DR

This study reveals how Sec61β helps maintain protein balance in cells by controlling protein production during ER stress, preventing harmful protein buildup.

## Contribution

The novel finding is that Sec61β uses ARIH1 to repress translation of specific mRNAs during ER stress, preventing overproduction of ERpQC substrates.

## Key findings

- Sec61β recruits ARIH1 and 4EHP to suppress translation of ERpQC substrates by inhibiting eIF4E binding to mRNA.
- Sec61β deficiency leads to excessive ERpQC substrate synthesis, reduced proteasome activity, and aggresome formation.
- Zebrafish with Sec61β deficiency show motor dysfunction, which is rescued by ARIH1 expression.

## Abstract

Disrupted proteostasis causes various degenerative diseases, and organelle homeostasis is therefore maintained by elaborate mechanisms. Endoplasmic reticulum (ER) stress-induced preemptive quality control (ERpQC) counteracts stress by reducing ER load through inhibiting the translocation of newly synthesized proteins into the ER for their rapid degradation in the cytoplasm. Here, we show that Sec61β, a translocon component, prevents the overproduction of ERpQC substrates, allowing for their efficient degradation by the proteasome. Sec61β inhibits the binding of translation initiation factor eIF4E to the mRNA 5ʹ cap structure by recruiting E3 ligase ARIH1 and eIF4E-homologous protein 4EHP, resulting in selective translational repression of ERpQC substrates. Sec61β deficiency causes overproduction of ERpQC substrates and reduces proteasome activity, leading to cytoplasmic aggresome formation. We also show that Sec61β deficiency causes motor dysfunction in zebrafish, which is restored by exogenous ARIH1 expression. Collectively, translational repression of ERpQC substrates by the Sec61β–ARIH1 complex contributes to maintain ER and cytoplasmic proteostasis.

Endoplasmic reticulum (ER) stress-induced pre-emptive quality control (ERpQC) contributes to the maintenance of proteostasis not only in the ER but also in the cytoplasm, thereby sustaining cellular function.

Under ER stress conditions, Derlin family proteins (Derlins) interact with the translocon component Sec61β.Sec61β recruits the E3 ligase ARIH1 and facilitates the association of 4EHP with the 5’ cap structure of ERpQC substrate mRNAs, suppressing their translation.Sec61β deficiency causes excessive synthesis of ERpQC substrates, reduced proteasome activity, and cytoplasmic aggresome formation, ultimately leading to motor dysfunction in zebrafish.

Under ER stress conditions, Derlin family proteins (Derlins) interact with the translocon component Sec61β.

Sec61β recruits the E3 ligase ARIH1 and facilitates the association of 4EHP with the 5’ cap structure of ERpQC substrate mRNAs, suppressing their translation.

Sec61β deficiency causes excessive synthesis of ERpQC substrates, reduced proteasome activity, and cytoplasmic aggresome formation, ultimately leading to motor dysfunction in zebrafish.

Endoplasmic reticulum (ER) stress-induced pre-emptive quality control (ERpQC) contributes to the maintenance of proteostasis not only in the ER but also in the cytoplasm, thereby sustaining cellular function.