Dysregulated ribosome quality control in human diseases

Abstract

Precise regulation of mRNA translation is of fundamental importance for maintaining homeostasis. Conversely, dysregulated general or transcript-specific translation, as well as abnormal translation events, have been linked to a multitude of diseases. However, driven by the misconception that the transient nature of mRNAs renders their abnormalities inconsequential, the importance of mechanisms that monitor the quality and fidelity of the translation process has been largely overlooked. In recent years, there has been a dramatic shift in this paradigm, evidenced by several seminal discoveries on the role of a key mechanism in monitoring the quality of mRNA translation - namely, Ribosome Quality Control (RQC) - in the maintenance of homeostasis and the prevention of diseases. Here, we will review recent advances in the field and emphasize the biological significance of the RQC mechanism, particularly its implications in human diseases.

Keywords: RQC; proteostasis; ribosome collisions; ribosome quality control; ribosome stalling.

Fig. 1

Ribosomal Quality Control (RQC) mechanism. When a translating ribosome stalls, for instance due to damaged nucleotides, the trailing ribosome collides into the stalled ribosome. These collision events are detected by the E3 ubiquitin ligase and RNA‐binding protein, ZNF598, which induces ubiquitination of several small ribosomal subunit (40S) proteins of the leading ribosome. Subsequently, the GIGYF2/4EHP translational repressor complex is recruited by ZNF598. 4EHP displaces the eIF4F complex on the 5′ cap, thereby preventing further rounds of translation initiation on the mRNA. The ASCC complex binds to the leading ribosome following its ubiquitination by ZNF598, splitting the ribosome into the ubiquitinated 40S and peptidyl‐tRNA‐bound 60S subunits through the helicase activity of ASCC3. Deubiquitination of the 40S subunit by OTUD3 and USP21 enables its recycling into the cellular pool. The RQC complex binds to the peptidyl‐tRNA‐bound 60S, and ANKZF1 is stimulated by ARB1 to cleave the CCA‐ bond between the nascent peptide and the tRNA, enabling their dissociation. NEMF displaces the ANKZF1 bound to 60S and promotes C‐terminal addition to the translation tail (CATylation) of the nascent peptide, while LTN1 polyubiquitinates the N‐terminal end of the nascent peptide. p97 is recruited to the ubiquitinated nascent peptide and, together with the NPLOC4 and UFDL1 cofactors, generates mechanical force through ATP hydrolysis that pulls the nascent peptide through the central pore of p97 and out of the 60S. The nascent peptide is subsequently shuttled to the proteasome and presented for degradation by p97, while the 60S subunit is recycled. The mRNA is cleaved by an endonuclease, Cue2 in yeast, and potentially its human homolog N4BP2, and subsequently degraded by the exonuclease activity of XRN1 (5′ to 3′) and the Exosome (3′ to 5′).

Fig. 2

Alternative Ribosome Quality Control pathways. (A) MKRN1 binds to cytosolic poly‐A binding protein PABC1 at premature polyadenylation sites on mRNA and ubiquitinates the uS10 (RPS10) subunit of 40S, inducing ribosomal stalling before the polyadenylated sequence is translated. This leads to ribosomal collision and initiates “canonical” RQC via ZNF598, as described in Fig. 1. (B) EDF1 binds to collided ribosomes, inducing a c‐JUN mediated transcriptional response, and recruits the GIGYF2/4EHP complex which inhibits cap‐dependent translation of the faulty mRNA. (C) GCN2 is recruited to collide ribosomes along with GCN1 and ABCF3, the human homolog of GCN20 in yeast, initiating the Integrated Stress Response (ISR) through phosphorylation of eIF2α. Phosphorylated eIF2α induces a general shutdown of cap‐dependent translation initiation but increases the translation of mRNAs encoding proteins involved in stress response. (D) ZAKα binds to collided ribosomes, inducing the Ribotoxic Stress Response (RSR) by activating stress‐activated protein kinases (SAPKs) p38 and JNK. Activation of these SAPKs promotes inflammation and stress responses, including cell cycle arrest and eventually apoptosis after strong and sustained signalling.