Autophagy cargo receptors are secreted via extracellular vesicles and particles in response to endolysosomal inhibition or impaired autophagosome maturation

Solvik, Tina; Nguyen, Tracy; Lin, Yu-Hsiu T.; Marsh, Timothy; Huang, Eric J.; Wiita, Arun P.; Debnath, Jayanta; Leidal, Andrew M.

doi:10.1101/2021.08.12.456045

Cited by 7 publications

(6 citation statements)

References 41 publications

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“…It is also well known that ferritin is secreted, and this secretion is enhanced in some diseases, including hemophagocytic lymphohistiocytosis and adult-onset Still’s disease ( Rosario et al, 2013 ). NCOA4 and ferritin can be secreted via extracellular vesicles ( Solvik et al, 2021 ; Yanatori et al, 2021 ). Thus, ferritin–NCOA4 condensates may be directed to both lysosomal degradation and secretion after incorporation into endosomes.…”

Section: Resultsmentioning

confidence: 99%

NCOA4 drives ferritin phase separation to facilitate macroferritinophagy and microferritinophagy

Ohshima

Yamamoto

Sakamaki

et al. 2022

Journal of Cell Biology

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A ferritin particle consists of 24 ferritin proteins (FTH1 and FTL) and stores iron ions within it. During iron deficiency, ferritin particles are transported to lysosomes to release iron ions. Two transport pathways have been reported: macroautophagy and ESCRT-dependent endosomal microautophagy. Although the membrane dynamics of these pathways differ, both require NCOA4, which is thought to be an autophagy receptor for ferritin. However, it is unclear whether NCOA4 only acts as an autophagy receptor in ferritin degradation. Here, we found that ferritin particles form liquid-like condensates in a NCOA4-dependent manner. Homodimerization of NCOA4 and interaction between FTH1 and NCOA4 (i.e., multivalent interactions between ferritin particles and NCOA4) were required for the formation of ferritin condensates. Disruption of these interactions impaired ferritin degradation. Time-lapse imaging and three-dimensional correlative light and electron microscopy revealed that these ferritin–NCOA4 condensates were directly engulfed by autophagosomes and endosomes. In contrast, TAX1BP1 was not required for the formation of ferritin–NCOA4 condensates but was required for their incorporation into autophagosomes and endosomes. These results suggest that NCOA4 acts not only as a canonical autophagy receptor but also as a driver to form ferritin condensates to facilitate the degradation of these condensates by macroautophagy (i.e., macroferritinophagy) and endosomal microautophagy (i.e., microferritinophagy).

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Section: Resultsmentioning

confidence: 99%

NCOA4 drives ferritin phase separation to facilitate macroferritinophagy and microferritinophagy

Ohshima

Yamamoto

Sakamaki

et al. 2022

Journal of Cell Biology

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“…It is well known that ferritin is secreted and this secretion is enhanced in some diseases, including hemophagocytic lymphohistiocytosis and adult-onset Still's disease (Rosario et al, 2013). Moreover, autophagy-related proteins such as NCOA4 were found to be secreted via extracellular vesicles (Solvik et al, 2021). Furthermore, a recent paper reported that ferritin secretion via extracellular vesicles depends on NCOA4 (Yanatori et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

NCOA4 drives ferritin phase separation to facilitate macroferritinophagy and endosomal microferritinophagy

Ohshima

Yamamoto

Sakamaki

et al. 2022

Preprint

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A ferritin particle consists of 24 ferritin proteins (FTH1 and FTL) and stores iron ions within it. During iron deficiency, ferritin particles are transported to lysosomes to release iron ions. Two transport pathways have been reported: macroautophagy and ESCRT-dependent endosomal microautophagy. Although the membrane dynamics of these pathways differ, both require NCOA4, which is thought to be an autophagy receptor for ferritin. However, the exact function of NCOA4 remains elusive. Here, we found that ferritin particles form liquid-like condensates in a NCOA4-dependent manner. Homodimerization of NCOA4 and interaction between FTH1 and NCOA4 (i.e., multivalent interactions between ferritin particles and NCOA4) were required for the formation of ferritin condensates. Disruption of these interactions impaired ferritin degradation. Time-lapse imaging and three-dimensional correlative light and electron microscopy revealed that these ferritin-NCOA4 condensates were directly engulfed by autophagosomes and endosomes. In contrast, TAX1BP1 was not required for the formation of ferritin-NCOA4 condensates but was required for their incorporation into autophagosomes and endosomes. These results suggest that NCOA4 acts not only as a canonical autophagy receptor but also as a driver to form ferritin condensates to facilitate the degradation of these condensates by macroautophagy (i.e., macroferritinophagy) and endosomal microautophagy (i.e., microferritinophagy).

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“…Furthermore, it was noted that these extracellular vesicles can be efficiently processed for antigen presentation on MHC class I and II molecules (73,74). Inhibition of lysosomal acidification or of the fusion machinery between autophagosomes and lysosomes leads to the release of vesicles that contain autophagy receptors, such as p62 and NBR1 (75,76). These receptors recruit most likely ubiquitinated protein aggregates of both long-and short-lived proteins (71) into autophagosomes whose inner membrane is then released for unconventional secretion after autophagosome fusion with multivesicular bodies (MVBs) and successive exocytosis from MVBs.…”

Section: Antigen Secretion With the Assistance Of The Macroautophagy ...mentioning

confidence: 99%

Canonical and Non-Canonical Functions of the Autophagy Machinery in MHC Restricted Antigen Presentation

Münz

2022

Front. Immunol.

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Macroautophagy delivers cytoplasmic constituents for lysosomal degradation. Since major histocompatibility complex (MHC) class II molecules sample peptides after lysosomal degradation for presentation to CD4+ T cells, it was originally described that these peptides can also originate from macroautophagy substrates. In recent years it has become clear that in addition to this canonical function of the macroautophagy machinery during MHC class II restricted antigen presentation at least parts of this machinery are also used to regulate phagocytosis of antigens, degradation of MHC class I molecules, and unconventional secretion of antigens in extracellular vesicles, including virus particles. This review discusses how both canonical and non-canonical functions of the macroautophagy machinery influence antigen presentation on MHC class I and II molecules to CD8+ and CD4+ T cells. A better understanding of the molecular mechanisms by which the macroautophagy machinery is distributed between its canonical and non-canonical functions should allow targeting of antigens to these different pathways to influence MHC restricted presentation during vaccination against infectious diseases and tumors.

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Autophagy cargo receptors are secreted via extracellular vesicles and particles in response to endolysosomal inhibition or impaired autophagosome maturation

Cited by 7 publications

References 41 publications

NCOA4 drives ferritin phase separation to facilitate macroferritinophagy and microferritinophagy

NCOA4 drives ferritin phase separation to facilitate macroferritinophagy and microferritinophagy

NCOA4 drives ferritin phase separation to facilitate macroferritinophagy and endosomal microferritinophagy

Canonical and Non-Canonical Functions of the Autophagy Machinery in MHC Restricted Antigen Presentation

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