Ribosome Quality Control (RQC) Project

Bottom line: ribosome quality control detects stalled and colliding
ribosomes, splits them, and destroys the incomplete nascent chain: ZNF598 and
EDF1 sense collisions, PELO-HBS1L and ABCE1 split the ribosome, and the NEMF-LTN1
RQC complex ubiquitinates the chain left on the 60S subunit. All 13 candidate
genes on this page now have complete gene reviews, made during the Proteostasis
batches, whose co-translational QC selection covers RQC, rather than under this
project; the stale "Stub" line has been cleared and the remaining module/GO-CAM
follow-up is tracked in
#3952. Across the
12 RQC genes (VCP excluded) the reviews assess 430 GOA rows: 276 ACCEPT, 95
KEEP_AS_NON_CORE, 20 REMOVE, 18 MARK_AS_OVER_ANNOTATED, 17 MODIFY and 4 NEW.
The 97 rows that use RQC-specific terms, such as rescue of stalled cytosolic ribosome (GO:0072344) and RQC complex (GO:1990112), were all accepted or
added; the corrections fall on generic protein binding rows and on off-pathway
terms such as DNA replication for ASCC2/ASCC3. No RQC module has been built yet,
although six production GO-CAMs in gocams/ already model parts of the pathway.

Overview

Ribosome quality control is a cytosolic surveillance pathway that detects stalled
and collided ribosomes during translation, represses defective messages,
disassembles stalled ribosomes, and targets incomplete nascent chains for
ubiquitin-dependent degradation. The gene-level reviews are now complete for the
human core on this page; the remaining work is to turn those reviewed functions
into a compact RQC module and reconcile them with existing GO-CAM pathway models.

Model Species

Primary: Homo sapiens (human)
- Best characterized in human and mammalian systems
- Links to neurodegenerative disease (ALS, etc.)

Core Pathway Architecture

1. Collision Sensors

Detect ribosome collisions:
- ZNF598 - Ubiquitinates collided ribosomes (RPS10, RPS20)
- EDF1 - Collision sensor, recruits GIGYF2
- GIGYF2 - Recruits 4EHP to repress translation

2. Ribosome Splitting

Disassemble stalled ribosomes:
- PELO - Dom34 homolog, promotes subunit splitting
- HBS1L - GTPase, works with PELO
- ABCE1 - ATPase that physically separates subunits

3. RQC Complex

Handles 60S-nascent chain complexes:
- NEMF - Recruits LTN1, stabilizes nascent chain
- LTN1 - E3 ubiquitin ligase (Listerin)
- TCF25 - RQC complex component
- ANKZF1 - Vms1 homolog, releases stalled peptides

4. mRNA Decay

Targets problematic mRNAs:
- No-go decay pathway genes

5. Downstream Quality Control

• VCP/p97 - Extracts ubiquitinated substrates
• Proteasome - Degrades aberrant proteins

Candidate Genes

Key Mechanistic Themes

• EDF1 as collision sensor (2020)
• ASCC complex structure and function
• Structural basis of ribosome splitting
• Links to neurodegeneration

Disease Relevance

• ALS/neurodegeneration (C9orf72 repeat expansions cause ribosome stalling)
• NEMF mutations cause neurological disease
• Proteostasis disorders

Project Status

• [x] Review all 13 candidate genes listed here
• [ ] Build an RQC module spanning ZNF598/EDF1 collision sensing,
  PELO-HBS1L-ABCE1 splitting and NEMF-LTN1 nascent-chain handling
  (#3952)
• [ ] Cross-check the six production GO-CAMs that already model parts of the
  pathway against the curated gene reviews
  (#3952)