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

Abstract

Translation-dependent quality control pathways such as no-go decay (NGD), non-stop decay (NSD) and nonsense-mediated decay (NMD) govern protein synthesis and proteostasis by resolving non-translating ribosomes and preventing the production of potentially toxic peptides derived from faulty and aberrant mRNAs. However, how translation is altered and the in vivo defects that arise in the absence of these pathways are poorly understood. Here, we show that the NGD/NSD factors Pelo and Hbs1l are critical for cerebellar neurogenesis but expendable for survival of these neurons after development. Analysis of mutant embryonic fibroblasts revealed translational pauses, alteration of signaling pathways, and translational reprogramming. Similar effects on signaling pathways, the translatome and cerebellar development were observed upon deletion of the NMD factor Upf2. These data reveal that these quality control pathways that function to mitigate errors at distinct steps in translation can evoke similar cellular responses.

Genetic deficiency of ribosomal rescue factor HBS1L causes retinal dystrophy associated with Pelota and EDF1 depletion

“…The intriguing aspect is why decreased protein expression of ribosomal rescue proteins, like HBS1L, elicits tissue-specific phenotypes. While Hbs1l tm1a/tm1a hypomorph mice do not display overt neurodegenerative phenotype (17), likely due to residual protein expression, an equivalent reduction of Hbs1l leads to retinal dystrophy in these mice. This difference may be partially explained by the extraordinary demand of protein synthesis for disc membrane and outer segment renewal in the retina (36)(37)(38) along with limited actively translating ribosomes due to Hbs1l depletion (16).…”

“…Additional mouse studies show that Hbs1l is required for mammalian embryogenesis and complete loss of Hbs1l results in embryonic lethality (17). We and others have shown that the deletion of Hbs1l leads to a tissue-specific reduction in its partner protein Pelo, which alters transcription regulation and reprograms the translatome (16,17).…”

“…A complete loss of Hbs1l leads to embryonic lethality (17), but marked reduction of Hbs1l (Hbs1l tm1a/tm1a ) is associated with a viable mouse model with phenotypic overlap (16). The Hbs1l transcripts and proteins were markedly reduced in the retinas of these mice (supplementary Figure S3) .…”

“…Subsequently, we showed that Hbs1l hypomorph mice (Hbs1l tm1a/tm1a , with residual expression of wild-type Hbs1l mRNA less than 10%) recapitulates several human phenotypes, including growth restriction, facial dysmorphism, and retinal pigmentation deposit (16). Additional mouse studies show that Hbs1l is required for mammalian embryogenesis and complete loss of Hbs1l results in embryonic lethality (17). We and others have shown that the deletion of Hbs1l leads to a tissue-specific reduction in its partner protein Pelo, which alters transcription regulation and reprograms the translatome (16,17).…”

“…While both proteins are critical for cerebellar neurogenesis in mice, they are dispensable for neuronal survival post-development (17).…”