NEMF mutations that impair ribosome-associated quality control are associated with neuromuscular disease

Abstract

A hallmark of neurodegeneration is defective protein quality control. The E3 ligase Listerin (LTN1/Ltn1) acts in a specialized protein quality control pathway—Ribosome-associated Quality Control (RQC)—by mediating proteolytic targeting of incomplete polypeptides produced by ribosome stalling, and Ltn1 mutation leads to neurodegeneration in mice. Whether neurodegeneration results from defective RQC and whether defective RQC contributes to human disease have remained unknown. Here we show that three independently-generated mouse models with mutations in a different component of the RQC complex, NEMF/Rqc2, develop progressive motor neuron degeneration. Equivalent mutations in yeast Rqc2 selectively interfere with its ability to modify aberrant translation products with C-terminal tails which assist with RQC-mediated protein degradation, suggesting a pathomechanism. Finally, we identify NEMF mutations expected to interfere with function in patients from seven families presenting juvenile neuromuscular disease. These uncover NEMF’s role in translational homeostasis in the nervous system and implicate RQC dysfunction in causing neurodegeneration.

Convergence of mammalian RQC and C-end rule proteolytic pathways via alanine tailing

“…Our finding of at least two E3 ligases that can act redundantly with Listerin in RQC, along with the conservation of C-terminal tailing as a proteolytic tagging mechanism in RQC from bacteria to mammals (this work; Lytvynenko et al, 2019;Sitron and Brandman, 2019) and the neurodegenerative phenotype of mice and humans with RQC mutations (Chu et al, 2009;Martin et al, 2020), implies that the products of failed translation pose a critical problem to cellular fitness. Along these lines, one direction of future work will be aimed at investigating the role of Pirh2 and CRL2 KLHDC10 in neurodegeneration caused by the Listerin mutation (Chu et al, 2009).…”

Ribosome states signal RNA quality control

“…By contrast, when there are more substantive problems with the mRNA such that the ORF is unlikely to generate a full-length protein product, then the cell targets the incomplete nascent peptide for decay and often inhibits further rounds of initiation before degrading the mRNA to minimize protein output (Brandman and Hegde, 2016). We know these steps are critical, as deletion of factors involved in these processes leads to the accumulation of protein aggregates and cell death in yeast (Bengtson and Joazeiro, 2010) and neurodegeneration in mammals (Ishimura et al, 2014;Martin et al, 2020).…”

Defects in translation-dependent quality control pathways lead to convergent molecular and neurodevelopmental pathology

“…Defects in translation and their translation-dependent quality control pathways impair cellular homeostasis and have been linked to proteotoxicity, changes in synaptic function, and neurodegeneration (Choe et al, 2016;Chu et al, 2009;Huang et al, 2017;Ishimura et al, 2014;Johnson et al, 2019;Kapur et al, 2020;Martin et al, 2020;Notaras et al, 2019;Terrey et al, 2020;Yonashiro et al, 2016). Here, we demonstrate that the ribosome rescue factors Pelo and Hbs1l, which are implicated in NSG and NGD, are critical for embryonic and brain development, but dispensable for neuronal survival in the adult brain.…”