Stress Granule Assembly Project

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 ALS and FTD.

Model Species

Primary: Homo sapiens (human)
- Major disease relevance (ALS, FTD)
- Well-characterized in human cells

Core Pathway Architecture

1. Core Nucleators

Proteins essential for stress granule assembly:
- 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 ALS/FTD:
- TARDBP (TDP-43) - RNA binding protein
- FUS - Fused in sarcoma
- HNRNPA1/A2B1 - hnRNPs
- ATXN2 - Ataxin-2

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 (~15-18)

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	ALS gene
HNRNPA1	P09651	RNA binding
ATXN2	Q99700	ALS modifier
VCP	P55072	Disassembly
PABPC1	P11940	Poly(A) binding

Key Recent Discoveries (2020+)

• G3BP1/2 as core nucleators (structural basis)
• Phase separation dynamics
• Stress granule-autophagy crosstalk
• Role in viral infection

Disease Relevance

• ALS (TDP-43, FUS, ATXN2 mutations)
• Frontotemporal dementia
• Viral infection
• Cancer (stress adaptation)

Project Status

• [ ] Stub - needs gene folder setup