Stress Granule Assembly Project
Bottom line: scoped, not yet started as a project. Stress granules are
membraneless RNA-protein condensates that form when translation initiation
stalls under stress; G3BP1/G3BP2 and TIA1/TIAL1 nucleate them, and several
amyotrophic lateral sclerosis/frontotemporal dementia proteins (TDP-43, FUS,
hnRNPA1/A2B1, ATXN2) partition into them. The
candidate table below lists 16 human genes, but there is no stress granule module and
the core nucleators G3BP1 and G3BP2 have not been reviewed. Seven candidates
already have reviews made for other projects (TIA1, TIAL1, USP10, TARDBP,
HNRNPA2B1, ATXN2, VCP). Existing stress-granule rows were accepted for TIA1
(8 rows, including stress granule assembly, GO:0034063), TARDBP, ATXN2, and
VCP (including stress granule disassembly, GO:0035617); TIAL1 adds stress
granule assembly as a NEW row. USP10's three negative regulation of stress
granule assembly rows were kept as non-core. Nine candidates, including
CAPRIN1, FUS, HNRNPA1 and PABPC1, are unreviewed. The related
CONDENSATES project covers how GO should represent
condensates in general.
Overview
Stress granules are membraneless organelles formed via liquid-liquid phase separation (LLPS) during cellular stress. They sequester stalled translation initiation complexes and are implicated in neurodegenerative diseases including amyotrophic lateral sclerosis and frontotemporal dementia.
Model Species
- Primary species: Homo sapiens (human)
- Major disease relevance (amyotrophic lateral sclerosis, frontotemporal dementia)
- Well-characterized in human cells
Core Pathway Architecture
1. Nucleators and TIA-family assembly factors
G3BP1/G3BP2 are core nucleators; TIA-family RNA-binding proteins also
contribute to stress-granule assembly, with TIAL1's independent scaffolding
requirement still open.
- G3BP1 - Core nucleator, Ras-GTPase activating SH3 binding protein
- G3BP2 - G3BP1 paralog
- TIA1 - T-cell intracellular antigen 1
- TIAR (TIAL1) - TIA1-related protein
2. RNA-Binding Proteins
Recruited to stress granules:
- PABPC1 - Poly(A) binding protein
- CAPRIN1 - G3BP interactor
- USP10 - G3BP interactor, deubiquitinase
- FMR1 (FMRP) - Fragile X protein
3. Disease-Associated Proteins
Mutated in amyotrophic lateral sclerosis or frontotemporal dementia:
4. Translation Machinery
- EIF2S1 (eIF2α) - Phosphorylation triggers SG assembly
- EIF4G1 - Translation initiation factor
- 40S ribosomal subunits
5. Disassembly Factors
- VCP (p97) - AAA+ ATPase
- Chaperones (HSP70 family)
Candidate Genes (16)
| Gene | UniProt | Function |
|---|---|---|
| G3BP1 | Q13283 | Core nucleator |
| G3BP2 | Q9UN86 | Core nucleator |
| TIA1 | P31483 | Nucleator |
| TIAL1 | Q01085 | TIAR |
| CAPRIN1 | Q14444 | G3BP interactor |
| USP10 | Q14694 | G3BP regulator |
| TARDBP | Q13148 | TDP-43 |
| FUS | P35637 | Disease gene |
| HNRNPA1 | P09651 | RNA binding |
| HNRNPA2B1 | P22626 | RNA binding |
| ATXN2 | Q99700 | Amyotrophic lateral sclerosis modifier |
| VCP | P55072 | Disassembly |
| PABPC1 | P11940 | Poly(A) binding |
| FMR1 | Q06787 | FMRP |
| EIF2S1 | P05198 | eIF2α |
| EIF4G1 | Q04637 | Translation initiation |
Key Recent Discoveries (2020+)
- G3BP1/2 as core nucleators (structural basis)
- Phase separation dynamics
- Stress granule-autophagy crosstalk
- Role in viral infection
Disease Relevance
- Amyotrophic lateral sclerosis (TDP-43, FUS, ATXN2 mutations)
- Frontotemporal dementia
- Viral infection
- Cancer (stress adaptation)
Project Status
- Complete: Cross-project reviews checked for TIA1, TIAL1, USP10, TARDBP,
HNRNPA2B1, ATXN2 and VCP - Future work: Fetch and review G3BP1, G3BP2, CAPRIN1, FUS, HNRNPA1, PABPC1, FMR1,
EIF2S1 and EIF4G1
(#3953) - Future work: Build a stress-granule module centered on G3BP1/G3BP2 nucleation and
VCP-dependent disassembly