Unconventional secretion of FABP4 by endosomes and secretory lysosomes

Villeneuve, Julien; Bassaganyas, Laia; Lepreux, Sébastien; Chirițoiu, Marioara; Costet, Pierre; Ripoche, Jean; Malhotra, Vivek; Schekman, Randy

doi:10.1083/jcb.201705047

Cited by 69 publications

(85 citation statements)

References 78 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Similar to most but not all UPS pathways tyrosine kinase triggered EV secretion of TACE was found to be GRASP‐dependent. TACE secretion was not observed in cells where GRASP55 was inactivated, and interestingly, could also be elicited in the absence of tyrosine kinase activation by forced GRASP55 overexpression.…”

Section: Discussionmentioning

confidence: 84%

Tyrosine phosphorylation directs TACE into extracellular vesicles via unconventional secretion

Zhao

Kesti

Uğurlu

et al. 2019

Traffic

View full text Add to dashboard Cite

When studying how HIV‐1 Nef can promote packaging of the proinflammatory transmembrane protease TACE (tumor necrosis factor‐α converting enzyme) into extracellular vesicles (EVs) we have revealed a novel tyrosine kinase‐regulated unconventional protein secretion (UPS) pathway for TACE. When TACE was expressed without its trafficking cofactor iRhom allosteric Hck activation by Nef triggered translocation of TACE into EVs. This process was insensitive to blocking of classical secretion by inhibiting endoplasmic reticulum (ER) to Golgi transport, and involved a distinct form of TACE devoid of normal glycosylation and incompletely processed for prodomain removal. Like most other examples of UPS this process was Golgi reassembly stacking protein (GRASP)‐dependent but was not associated with ER stress. These data indicate that Hck‐activated UPS provides an alternative pathway for TACE secretion that can bypass iRhom‐dependent ER to Golgi transfer, and suggest that tyrosine phosphorylation might have a more general role in regulating UPS.

show abstract

Section: Discussionmentioning

confidence: 84%

Tyrosine phosphorylation directs TACE into extracellular vesicles via unconventional secretion

Zhao

Kesti

Uğurlu

et al. 2019

Traffic

View full text Add to dashboard Cite

show abstract

“…Thus, it is difficult to exclude the possibility that the previously assumed “lysosomal secretion” actually originates from late endosomes or a population of late endosomes. Consistent with this view, the cytoplasmic fatty acid binding protein 4 (FABP4) was recently added to the list of clients of “lysosomal secretion”, but the cargo was actually found within both endosomes and lysosomes prior to secretion [ 68 ]. Because of the difficulty in drawing a clear line between late endosomes and lysosomes, we propose the term “endo-lysosome” to describe the acidified UPS compartment with characteristics of lysosomes and late endosomes.…”

Section: Lysosome or Endosome As A Secretory Compartment?mentioning

confidence: 99%

The Roles of Endo-Lysosomes in Unconventional Protein Secretion

Lee

2018

Cells

View full text Add to dashboard Cite

Protein secretion in general depends on signal sequence (also named leader sequence), a hydrophobic segment located at or close to the NH2-terminus of a secretory or membrane protein. This sequence guides the entry of nascent polypeptides into the lumen or membranes of the endoplasmic reticulum (ER) for folding, assembly, and export. However, evidence accumulated in recent years has suggested the existence of a collection of unconventional protein secretion (UPS) mechanisms that are independent of the canonical vesicular trafficking route between the ER and the plasma membrane (PM). These UPS mechanisms export soluble proteins bearing no signal sequence. The list of UPS cargos is rapidly expanding, along with the implicated biological functions, but molecular mechanisms accountable for the secretion of leaderless proteins are still poorly defined. This review summarizes our current understanding of UPS mechanisms with an emphasis on the emerging role of endo-lysosomes in this process.

show abstract

“…However, although mHTT aggregates do induce autophagy [ 134 ], there is no evidence that mHTT secretion is dependent on autophagy. On the other hand, a very recent report on the unconventional secretion of cytoplasmic fatty acid binding protein 4 (FABP4) has illustrated the existence of another pathway that is independent of GRASP and autophagy, but involves cargo enclosure within endosomes and secretory lysosomes [ 135 ]. Regulated exocytosis based on lysosome-like organelles has been documented extensively in immune cells [ 136 ], but even conventional lysosomes in many cell types could apparently fuse with the plasma membrane in response to increases in intracellular free Ca 2+ concentration in a calcium sensor synaptotagmin-dependent manner (reminiscent of synaptic vesicles in axon terminals) [ 137 ].…”

Section: Mechanisms Underlying the Extracellular Secretion Of Mhttmentioning

confidence: 99%

Unconventional Secretion and Intercellular Transfer of Mutant Huntingtin

Tang

2018

Cells

View full text Add to dashboard Cite

The mechanism of intercellular transmission of pathological agents in neurodegenerative diseases has received much recent attention. Huntington’s disease (HD) is caused by a monogenic mutation in the gene encoding Huntingtin (HTT). Mutant HTT (mHTT) harbors a CAG repeat extension which encodes an abnormally long polyglutamine (polyQ) repeat at HTT’s N-terminus. Neuronal pathology in HD is largely due to the toxic gain-of-function by mHTT and its proteolytic products, which forms both nuclear and cytoplasmic aggregates that perturb nuclear gene transcription, RNA splicing and transport as well cellular membrane dynamics. The neuropathological effects of mHTT have been conventionally thought to be cell-autonomous in nature. Recent findings have, however, indicated that mHTT could be secreted by neurons, or transmitted from one neuronal cell to another via different modes of unconventional secretion, as well as via tunneling nanotubes (TNTs). These modes of transmission allow the intercellular spread of mHTT and its aggregates, thus plausibly promoting neuropathology within proximal neuronal populations and between neurons that are connected within neural circuits. Here, the various possible modes for mHTT’s neuronal cell exit and intercellular transmission are discussed.

show abstract

Unconventional secretion of FABP4 by endosomes and secretory lysosomes

Cited by 69 publications

References 78 publications

Tyrosine phosphorylation directs TACE into extracellular vesicles via unconventional secretion

Tyrosine phosphorylation directs TACE into extracellular vesicles via unconventional secretion

The Roles of Endo-Lysosomes in Unconventional Protein Secretion

Unconventional Secretion and Intercellular Transfer of Mutant Huntingtin

Contact Info

Product

Resources

About