MISTERMINATE Mechanistically Links Mitochondrial Dysfunction with Proteostasis Failure

Abstract

Highlights d Longer forms of respiratory chain proteins accumulate under mitochondrial stress d Such proteins are formed by co-translational C-terminal extension (MISTERMINATE) d Such proteins can impair respiratory chain and also form cytosolic aggregates d MISTERMINATE links mitochondrial dysfunction with proteostasis failure in disease

Aggregation of CAT tails blocks their degradation and causes proteotoxicity in S. cerevisiae

“…To preserve threonine content, the fitness benefit from this threonine-mediated CAT tail function would need to outweigh any fitness deficits arising from CAT tail aggregation. Given the recent discovery of Rqc2 homologs that incorporate different amino acids into CAT tails [24,34], domain-swapping between these homologs to bias CAT tail amino acid content may assist in determining the function of threonine in CAT tails in future studies. Broadly, understanding how the variable amino acid composition of CAT tails has evolved to meet physiological demands in different organisms may prove a fruitful area of research.…”

“…In mice, a hypomorphic LTN1 allele induces a progressive neurodegeneration that shares phenotypic similarities with amyotrophic lateral sclerosis (ALS) [32]. It is possible that degenerating neurons in these LTN1-hypomorphic mice harbor toxic CAT tail aggregates, as has been observed in a Drosophila model of Parkinson Disease [34]. As the connection between the phenotypes in these disease models and human disease becomes more clear, future studies can focus on strategies to mitigate toxicity associated with compromised Ltn1.…”

“…Salmonella enterica and Streptococcus pneumoniae) [28][29][30][31]. In metazoan eukaryotes, mutations to LTN1 or perturbations that introduce large influxes of RQC substrates lead to neurodegeneration [32][33][34]. Each of these phenotypes highlights the central role that tmRNA and Ltn1 play in maintaining protein homeostasis and avoiding the toxicity associated with compromised co-translational quality control.…”

“…Rqc2 homologs bind the large ribosomal subunit and direct it to elongate the incomplete polypeptide's C-terminus with either alanine ("Ala tails" in prokaryotes) or both alanine and threonine residues ("CAT tails" in yeast) [24,36,37]. Metazoan CAT tails may include a more diverse repertoire of amino acids [34]. These extensions, made without a small subunit or mRNA, act as "degrons" to mark incomplete polypeptides for degradation by the bacterial protease ClpXP or the eukaryotic proteasome [24,35].…”

“…Loss of Ltn1 function results in a buildup of CAT-tailed ("CATylated") proteins [36]. The CAT tails on these proteins can homo-typically associate and form aggregates of CATylated proteins, which have been observed in yeast and metazoans [26,34,38,39]. The presence of threonine in yeast CAT tails increases their aggregation propensity [38].…”