| Pathway/Process | SGTA Role | Key Partner Proteins | Substrates | Biological Outcome |
|---|---|---|---|---|
| GET/TRC pathway for tail-anchored protein targeting | Cytosolic co-chaperone and early triage factor that captures hydrophobic tail-anchored (TA) clients after synthesis, forms a pre-targeting complex, and promotes handoff to TRC40/Get3 for ER delivery; its TPR domain also links upstream Hsp70 input to downstream targeting machinery (pqac-00000002, pqac-00000007, pqac-00000008, pqac-00000014, pqac-00000015, pqac-00000018) | Hsp70/Hsc70, BAG6, UBL4A, TRC35, TRC40/Get3, WRB, CAML (pqac-00000002, pqac-00000007, pqac-00000008, pqac-00000014, pqac-00000015, pqac-00000018) | ER-destined TA proteins with hydrophobic C-terminal transmembrane domains; examples include syntaxin-5 and other TRC40 clients (pqac-00000002, pqac-00000007, pqac-00000012, pqac-00000015) | Efficient shielding of hydrophobic segments, selective ER targeting and membrane insertion, reduced aggregation/mistargeting, and productive membrane protein biogenesis (pqac-00000007, pqac-00000008, pqac-00000014, pqac-00000015) |
| BAG6-mediated protein quality control / degradation | Uncommitted client holder and antagonist/modulator of degradation that cooperates with BAG6-dependent quality control; SGTA-bound hydrophobic clients can be transferred to BAG6 for ubiquitination or rescued by deubiquitination, thereby setting the balance between degradation and rescue/retargeting (pqac-00000003, pqac-00000008, pqac-00000011, pqac-00000012, pqac-00000018) | BAG6, UBL4A, TRC35, RNF126, USP5, proteasome/ADRM1-Rpn13, Hsp70/Hsp90 (pqac-00000002, pqac-00000008, pqac-00000011, pqac-00000012, pqac-00000018) | Mislocalized membrane proteins (MLPs), aberrant TA proteins, other hydrophobic precursors exposing transmembrane segments in the cytosol; MAVS is an endogenous example linked to BAG6/SGTA handling (pqac-00000002, pqac-00000008, pqac-00000011, pqac-00000012) | Cytosolic protein quality control by either BAG6/RNF126-dependent ubiquitination and proteasomal degradation or delayed degradation/possible rescue through SGTA-associated deubiquitination; overall prevention of toxic hydrophobic protein accumulation (pqac-00000003, pqac-00000008, pqac-00000011, pqac-00000012) |
| ER protein reflux (ERCYS) | Cytosolic HSC70 co-chaperone required for ER-to-cytosol reflux of selected ER proteins during stress; acts with ER membrane J-domain proteins to receive/export refluxed clients and promote their cytosolic handling (pqac-00000006) | HSC70, DNAJB12, DNAJB14 (pqac-00000006) | Refluxed ER proteins, including AGR2 in the reported mammalian ERCYS pathway (pqac-00000006) | Stress-responsive ER protein reflux to the cytosol, altered p53 regulation, and increased cancer cell fitness/survival in the described model system (pqac-00000006) |
| HSP70-dependent substrate capture | Receives hydrophobic clients from cytosolic Hsp70 through its TPR domain; functions downstream of Hsp70 in a substrate-funneling cascade that preserves client solubility and targeting competence before transfer to GET/TRC machinery (pqac-00000006, pqac-00000009, pqac-00000013, pqac-00000018) | Hsp70/Hsc70, J-domain proteins, Get4/Get5 or BAG6-complex components, Get3/TRC40 (pqac-00000006, pqac-00000009, pqac-00000013, pqac-00000018) | Newly synthesized hydrophobic TA proteins and related membrane protein clients whose exposed helices are aggregation-prone in the cytosol (pqac-00000009, pqac-00000013, pqac-00000018) | Maintains substrate solubility, minimizes aggregation, improves loading onto SGTA/Sgt2 and subsequent transfer to Get3/TRC40, thereby increasing targeting fidelity and biogenesis efficiency (pqac-00000009, pqac-00000013, pqac-00000014) |


*Table: This table summarizes the main biochemical pathways in which SGTA functions, emphasizing its roles in tail-anchored protein targeting, cytosolic quality control, ER protein reflux, and HSP70-linked substrate handling. It is useful for connecting SGTA’s molecular interactions to specific substrates and biological outcomes.*