The trinity of ribosome-associated quality control and stress signaling for proteostasis and neuronal physiology

Abstract

Translating ribosomes accompany co-translational regulation of nascent polypeptide chains, including subcellular targeting, protein folding, and covalent modifications. Ribosome-associated quality control (RQC) is a co-translational surveillance mechanism triggered by ribosomal collisions, an indication of atypical translation. The ribosome-associated E3 ligase ZNF598 ubiquitinates small subunit proteins at the stalled ribosomes. A series of RQC factors are then recruited to dissociate and triage aberrant translation intermediates. Regulatory ribosomal stalling may occur on endogenous transcripts for quality gene expression, whereas ribosomal collisions are more globally induced by ribotoxic stressors such as translation inhibitors, ribotoxins, and UV radiation. The latter are sensed by ribosome-associated kinases GCN2 and ZAKα, activating integrated stress response (ISR) and ribotoxic stress response (RSR), respectively. Hierarchical crosstalks among RQC, ISR, and RSR pathways are readily detectable since the collided ribosome is their common substrate for activation. Given the strong implications of RQC factors in neuronal physiology and neurological disorders, the interplay between RQC and ribosome-associated stress signaling may sustain proteostasis, adaptively determine cell fate, and contribute to neural pathogenesis. The elucidation of underlying molecular principles in relevant human diseases should thus provide unexplored therapeutic opportunities. [BMB Reports 2021; 54(9): 439-450]

Molecular basis of neurodegeneration in a mouse model of Polr3-related disease

“…Accordingly, the Polr3a mutation is predicted to compromise translation efficiency and change the frequency and sites of ribosome pausing and/or stalling. These events can trigger ISR induction via protein misfolding or unresolved ribosome collisions (Costa-Mattioli and Walter 2020 ; Park et al 2021 ). We propose that in the context of Polr3-related disease, chronic ISR activation ultimately fails to restore cellular homeostasis, and thus leads to neurodegeneration through amplification of the IR and activation of cell death pathways (Costa-Mattioli and Walter 2020 ).…”

Molecular basis of neurodegeneration in a mouse model ofPolr3-related disease

“…Accordingly, the Polr3a mutation is predicted to compromise translation efficiency and change the frequency and sites of ribosome pausing and/or stalling. These events can trigger ISR induction via protein misfolding or unresolved ribosome collisions (Costa-Mattioli and Walter 2020; Park et al 2021).…”

“…Accordingly, the Polr3a mutation is predicted to compromise translation efficiency and change the frequency and sites of ribosome pausing and/or stalling. These events can trigger ISR induction via protein misfolding or unresolved ribosome collisions ( Costa-Mattioli and Walter 2020 ; Park et al 2021 ). We propose that in the context of Polr3 -related disease, chronic ISR activation ultimately fails to restore cellular homeostasis, and thus leads to neurodegeneration through amplification of the IR and activation of cell death pathways ( Costa-Mattioli and Walter 2020 ).…”

SUMO pathway is required for ribosome biogenesis

“…These SUMO modifications are tightly regulated by SUMO-specific proteases, leading to regulation of gene expression, localization, and function as well as proteolytic control of target proteins during ribosome maturation. Functionally healthy ribosomes are vital for cell survival, and several mutations in ribosomes or ribosome assembly factors have been found to be lethal ( 61 , 62 ). Especially, specific defects in ribosome biogenesis or function could cause various clinical abnormalities, including skin and bone marrow failure syndromes such as X-linked dyskeratosis congenita and Schwachman-Diamond syndrome ( 63 , 64 ).…”