Abstract
Ribosome stalling during translation can potentially be harmful, and is surveyed by a conserved quality control pathway that targets the associated mRNA and nascent polypeptide chain (NC). In this pathway, the ribosome-associated quality control (RQC) complex promotes the ubiquitylation and degradation of NCs remaining stalled in the 60S subunit. NC stalling is recognized by the Rqc2/Tae2 RQC subunit, which also stabilizes binding of the E3 ligase, Listerin/ Ltn1. Additionally, Rqc2 modifies stalled NCs with a carboxy-terminal, Ala-and Thr-containing extension—the’CAT tail’. However, the function of CAT tails and fate of CAT tail-modified (’CATylated’) NCs has remained unknown. Here we show that CATylation mediates formation of detergent-insoluble NC aggregates. CATylation and aggregation of NCs could be observed either by inactivating Ltn1 or by analyzing NCs with limited ubiquitylation potential, suggesting that inefficient targeting by Ltn1 favors the Rqc2-mediated reaction. These findings uncover a translational stalling-dependent protein aggregation mechanism, and provide evidence that proteins can become specifically marked for aggregation.
Original language | English (US) |
---|---|
Article number | e11794 |
Journal | eLife |
Volume | 5 |
Issue number | MARCH2016 |
DOIs | |
State | Published - Mar 4 2016 |
Funding
We thank J Warner, A van Hoof, R Kopito, O Brandman, and S Lindquist for reagents. EBT gratefully acknowledges the Brazilian Council for Scientific and Technological Development (CNPq) for a Post-doctoral Fellowship. MK was supported by the Hartmut Hoffmann-Berling International Graduate School of Molecular and Cellular Biology (HBIGS). JNS gratefully acknowledges the NRSA for Post-doctoral Fellowship F32AG039127. Work in the Joazeiro laboratory was supported by NIH R01 grants NS075719 from the National Institute of Neurological Disorders and Stroke (NINDS) and CA152103 from the National Cancer Institute (NCI). Work in the Yates laboratory was supported by NIH grants P41 GM103533 and R01 MH067880. Work in the Craig laboratory was supported by NIH R01 grant GM31107 from the National Institute of General Medical Sciences (NIGMS). Work in the Bukau and Joazeiro (ZMBH) laboratories was supported in part by a grant of the Deutsche For-schungsgemeinschaft (SFB1036). This is manuscript 29225 from The Scripps Research Institute.
ASJC Scopus subject areas
- General Biochemistry, Genetics and Molecular Biology
- General Immunology and Microbiology
- General Neuroscience