Trafficking of a multifunctional protein by endosomal microautophagy: linking two independent unconventional secretory pathways
Abstract
During physiologic stresses, like micronutrient starvation, infection, and cancer, the cytosolic moonlighting protein glyceraldehyde‐3‐phosphate dehydrogenase (GAPDH) is trafficked to the plasma membrane (PM) and extracellular milieu (ECM). Our work demonstrates that GAPDH mobilized to the PM, and the ECM does not utilize the classic endoplasmic reticulum–Golgi route of secretion; instead, it is first selectively translocated into early and late endosomes from the cytosol via microautophagy. GAPDH recruited to this common entry point is subsequently delivered into multivesicular bodies, leading to its membrane trafficking through secretion via exosomes and secretory lysosomes. We present evidence that both pathways of GAPDH membrane trafficking are up‐regulated upon iron starvation, potentially by mobilization of intracellular calcium. These pathways also play a role in clearance of misfolded intracellular polypeptide aggregates. Our findings suggest that cells build in redundancy for vital cellular pathways to maintain micronutrient homeostasis and prevent buildup of toxic intracellular misfolded protein refuse.—Chauhan, A. S., Kumar, M., Chaudhary, S., Dhiman, A., Patidar, A., Jakhar, P., Jaswal, P., Sharma, K., Sheokand, N., Malhotra, H., Raje, C. I., Raje. M. Trafficking of a multifunctional protein by endosomal microautophagy: linking two independent unconventional secretory pathways. FASEB J. 33, 5626–5640 (2019). www.fasebj.org
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GAPDH becomes associated with exosomes during formation of intraluminal vesicles and exocytosis of exosomes is one pathway for secretion of GAPDH from cells.
“Recently, it has been observed that GAPDH becomes associated with exosomes during formation of intraluminal vesicles and that exocytosis of exosomes represents one pathway for secretion of GAPDH from cells, a process that is enhanced when cells are depleted of iron34.”
From GAPDH controls extracellular vesicle biogenesis and enhances the therapeutic potential of EV mediated siRNA delivery to the brain (2021) · cites this paper as [34]
GAPDH-GFP is predominantly associated with non-EV protein fractions, suggesting non-vesicular routes of GAPDH secretion.
“Analysis of GAPDH-GFP fluorescence from EVs and non-EV protein fractions reflected predominant association of GAPDH-GFP in the non-EV protein fractions, suggesting the existence of non-vesicular routes of GAPDH secretion, consistent with reports from others (Fig. 2g)34,43.”
From GAPDH controls extracellular vesicle biogenesis and enhances the therapeutic potential of EV mediated siRNA delivery to the brain (2021) · cites this paper as [34]
Cytosolic GAPDH associates with ILVs in early and late endosomes of human cells through endosomal microautophagy involving ESCRT machinery and HSC70.
“Recently, it has been demonstrated that cytosolic GAPDH associates with ILVs in early and late-endosomes of human cells through the process of endosomal microautophagy, which involves the ESCRT machinery and HSC70 (Heat shock cognate 71 kDa) protein34.”
From GAPDH controls extracellular vesicle biogenesis and enhances the therapeutic potential of EV mediated siRNA delivery to the brain (2021) · cites this paper as [34]
GAPDH is secreted on exosomes and, through interaction with transferrin and lactoferrin, can act as a sponge permitting uptake of free iron.
“This GAPDH is secreted on exosomes and through its interaction with transferrin and lactoferrin can act as a sponge, which permits the uptake of free iron.”
From GAPDH controls extracellular vesicle biogenesis and enhances the therapeutic potential of EV mediated siRNA delivery to the brain (2021) · cites this paper as [34]
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Self-citationBoradia, V. M., Malhotra, H., Thakkar, J. S., Tillu, V. A., Vuppala, B., Patil, P., Sheokand, N., Sharma, P., Chauhan, A. S., Raje, M., et al. (2014) · Nature Communications · doi:10.1038/ncomms5730 · Cited by 108 · see citing works
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Dar, G. H., Mendes, C. C., Kuan, W.-L., Speciale, A. A., Conceição, M., Görgens, A., Uliyakina, I., Lobo, M. J., Lim, W. F., EL Andaloussi, S., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-27056-3 · Cited by 100 · see citing works
- Authors
- Chauhan, A. S., Kumar, M., Chaudhary, S., Dhiman, A., Patidar, A., Jakhar, P., Jaswal, P., Sharma, K., Sheokand, N., Malhotra, H., Raje, C. I., & Raje, M.
- Affiliations
- Institute of Microbial Technology (IN)
- National Institute of Pharmaceutical Education and Research (IN)
- Corresponding author
- Raje, Manoj
- ORCID
- Venue
- The FASEB Journal
- Publisher
- Wiley
- Published
- 2019-01-14
- Volume
- 33
- Issue
- 4
- Pages
- 5626-5640
- ISSN
- 0892-6638 (ISSN-L)
- 1530-6860
- OpenAlex
- W2909042253
- Cited by
- 29
- References
- 7
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 1 · 2023: 3 · 2022: 3 · 2021: 7 · 2020: 5 · 2019: 1
- FWCI
- 2.12
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The FASEB Journal (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- glyceraldehyde-3-phosphate dehydrogenase, moonlighting proteins, unconventional secretion, exosomes, secretory lysosomes, multivesicular bodies, iron starvation, intracellular calcium, protein misfolding, protein clearance, micronutrient homeostasis, plasma membrane trafficking, extracellular matrix
- MeSH terms
- Microautophagy, Animals, Autophagy, Cell Line, Cell Membrane, Cell Movement, Cytosol, Endoplasmic Reticulum, Glyceraldehyde-3-Phosphate Dehydrogenases, Golgi Apparatus, Lysosomes, Endosomes, Up-Regulation, Protein Transport, Mice, Exosomes, Secretory Pathway, Multivesicular Bodies
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