Module 6 · Frontier
Unconventional Protein Secretion
Not every secreted protein follows the classical ER-Golgi-PM pathway. A growing list of cytosolic proteins without signal peptides — FGF2, IL-1β, HMGB1, tau, and several others — exit the cell via unconventional protein secretion (UPS). Four mechanistic types have been distinguished. Understanding UPS has become urgent because many disease-relevant cytokines and neurodegeneration-associated proteins exit by these routes.
1. UPS Type I: Direct PM Translocation
A cytosolic protein directly inserts into the inner leaflet of the plasma membrane and translocates to the outside. Classic example: FGF2. Mechanism (Steringer & Nickel 2018): FGF2 binds PI(4,5)P2 in the inner leaflet, oligomerises, and forms a lipidic pore through which monomers flip to the outer leaflet where they are captured by heparan-sulphate proteoglycans. The protein is secreted without ever entering a membrane-bound compartment.
Other type-I candidates: HIV-1 Tat, some homeodomain transcription factors that function extracellularly (engrailed), tau in some neurodegenerative models. All involve pore-forming oligomerisation at the inner PM leaflet.
2. UPS Type II: ABC-Transporter-Mediated
Used by some peptides and lipidated proteins: an ABC transporter family member (e.g., ABCB1, ABCG2) directly transfers cytosolic cargo across the plasma membrane at the expense of ATP. Best-documented example: the yeast a-factor pheromone, secreted by Ste6 ABC transporter. Less studied in mammals but implicated in some lipidated peptide secretions.
3. UPS Type III: Autophagy/Endosome-Based
The best-studied UPS pathway. Cytosolic cargo is engulfed by a double-membrane autophagosome, which then fuses with an endosome or the plasma membrane to release contents. IL-1β (interleukin-1β) uses this route: pro-IL-1β is synthesised as a cytosolic pro-form, cleaved by caspase-1 in the inflammasome, and released through the gasdermin-D pore and/or through autophagic secretion in many cell types (Zhang 2020, Dupont 2011).
Other cargoes via this route: HMGB1 (damage-associated molecular pattern), IL-18, some viral proteins. In yeast, Acb1 (Acyl-CoA binding protein) secretion occurs via a related “CUPS” (compartment for unconventional protein secretion) compartment that forms during starvation — the Malhotra lab’s work.
4. UPS Type IV: Golgi-Bypassing Signal-Peptide-Bearing Proteins
Some signal-peptide-bearing proteins enter the ER as expected but bypass the Golgi en route to the PM. Classic example: the CFTR F508del rescue pathway under some conditions routes through a GRASP-dependent alternative secretory route that avoids the classical Golgi glycosylation. This was one of the first evidences of GRASP-mediated UPS. The pathway is also exploited by some viral glycoproteins.
5. Inflammatory Consequences
UPS is overrepresented among inflammatory mediators:
- IL-1β, IL-18: inflammasome-dependent UPS Type III.
- HMGB1: released from dying cells as a DAMP.
- FGF2: pro-angiogenic, UPS Type I.
- Galectins 1, 3, 9: extracellular immunomodulation without ER-Golgi transit.
The pharmacological consequence: conventional secretion inhibitors (BFA, Golgi-targeting drugs) spare these molecules. Anti-IL-1β biologics (anakinra, canakinumab) have been far more effective than expected in inflammatory conditions partly because they act on a pathway that bypasses conventional drug-accessible secretion checkpoints.
6. Course Synthesis
Seven modules traced the Golgi from its 1898 silver-nitrate discovery through the cisternal-maturation-vs-vesicular-transport debate, COPI/COPII vesicle machinery, glycosylation biology, mitotic dynamics, congenital disorders of glycosylation, and unconventional secretion. The Golgi emerges as the cell’s central sorting and modification organelle — the machine that ensures that every protein not only folds correctly (the ER’s job) but ends up at the right destination with the right modifications. Its diseases (CDG, mucolipidoses) and its tumour biology (aberrant glycosylation) guarantee its continued therapeutic relevance.