CoChat
Sign Up
Cited by 129Autophagy in Disease and TherapyInflammasome and immune disordersImmune Response and Inflammation

Secretory versus degradative autophagy: unconventional secretion of inflammatory mediators

Open access
Jiang, Shanya, Dupont, Nicolas, Castillo, Eliseo F., Deretic, Vojo·2013·Journal of Innate Immunity
DOI 10.1159/000346707PMC PMC3723810
Open this paper in CoChat — free account

Abstract

Autophagy (macroautophagy) is often defined as a degradative process and a tributary of the lysosomal pathway. In this context, autophagy carries out cytoplasmic quality control and nutritional functions by removing defunct or disused organelles, particulate targets and invading microbes, and by bulk digestion of the cytoplasm. However, recent studies indicate that autophagy surprisingly affects multiple secretory pathways. Autophagy participates in extracellular delivery of a number of cytosolic proteins that do not enter the conventional secretory pathway via the Golgi apparatus but are instead unconventionally secreted directly from the cytosol. In mammalian cells, a prototypical example of this manifestation of autophagy is the unconventional secretion of a major proinflammatory cytokine, IL-1β. This review examines the concept of secretory autophagy and compares and contrasts the role of autophagy in the secretion of IL-1α and IL-1β. Although IL-1α and IL-1β have closely related extracellular inflammatory functions, they differ in intracellular activation, secretory mechanisms and how they are affected by autophagy. This example indicates that the role of autophagy in secretion is more complex, at least in mammalian cells, than the simplistic view that autophagosomes provide carriers for unconventional secretion of cytosolic proteins.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1159/000346707

Cites

7 of 7 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • IL-18 trafficking is similar to that of IL-1β, with secretory autophagy playing a major role in its release.

    “IL-18 trafficking is similar to that of IL-1β, with secretory autophagy also playing a major role in its release (35, 36).”

    From Macrophage Cytokines: Involvement in Immunity and Infectious Diseases (2014) · cites this paper as [36]

    The section on IL-1β secretion and inflammasome activation says secretory autophagy contributes to the release of both IL-1β and IL-18. It does not establish a major role in IL-18 release; for IL-1β, it describes the secretory contribution as transient during acute activation and masked under steady-state conditions. Page numbers are not provided in the supplied copy. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • Autophagy mediates the secretion of proteins such as IL-1β and IL-18 that lack a leader peptide.

    “Autophagy has also been recognized to mediate the secretion of proteins (34) – such as IL-1β and IL-18 (35, 36) – that would otherwise not enter the classical secretory pathway due to lack of a leader peptide.”

    From Macrophage Cytokines: Involvement in Immunity and Infectious Diseases (2014) · cites this paper as [36]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 50

  1. [1]Manjithaya R Anjard C Loomis WF Subramani S 2010 Unconventional secretion of Pichia pastoris Acb1 is dependent on GRASP protein, peroxisomal functions, and autophagosome formation J Cell Biol 188 537 546 20156962 PMC2828923
  2. [2]Bruns C McCaffery JM Curwin AJ Duran JM Malhotra V 2011 Biogenesis of a novel compartment for autophagosome-mediated unconventional protein secretion J Cell Biol 195 979 992 22144692 PMC3241719
  3. [3]Duran JM Anjard C Stefan C Loomis WF Malhotra V 2010 Unconventional secretion of Acb1 is mediated by autophagosomes J Cell Biol 188 527 536 20156967 PMC2828925
  4. [5]Deretic V Jiang S Dupont N 2012 Autophagy intersections with conventional and unconventional secretion in tissue development, remodeling and inflammation Trends in cell biology 22 397 406 22677446 PMC3408825
  5. [6]Rabouille C Malhotra V Nickel W 2012 Diversity of unconventional protein secretion Journal of Cell Science In press 23377655
  6. [7]Shorter J Watson R Giannakou ME Clarke M Warren G Barr FA 1999 GRASP55, a second mammalian GRASP protein involved in the stacking of Golgi cisternae in a cell-free system Embo J 18 4949 4960 10487747 PMC1171566
  7. [8]Cabral M Anjard C Malhotra V Loomis WF Kuspa A 2010 Unconventional secretion of AcbA in Dictyostelium discoideum through a vesicular intermediate Eukaryot Cell 9 1009 1017 20472692 PMC2901666
  8. [9]Kinseth MA Anjard C Fuller D Guizzunti G Loomis WF Malhotra V 2007 The Golgi-associated protein GRASP is required for unconventional protein secretion during development Cell 130 524 534 17655921
  9. [10]Nickel W Rabouille C 2009 Mechanisms of regulated unconventional protein secretion Nat Rev Mol Cell Biol 10 148 155 19122676
  10. [11]Giuliani F Grieve A Rabouille C 2011 Unconventional secretion: a stress on GRASP Current opinion in cell biology 23 498 504 21571519
  11. [12]Mizushima N Yoshimori T Ohsumi Y 2011 The role of atg proteins in autophagosome formation Annual review of cell and developmental biology 27 107 132 21801009
  12. [13]Rubinsztein DC Codogno P Levine B 2012 Autophagy modulation as a potential therapeutic target for diverse diseases Nature reviews Drug discovery 11 709 730 PMC3518431 22935804
  13. [14]Mizushima N Komatsu M 2011 Autophagy: renovation of cells and tissues Cell 147 728 741 22078875
  14. [15]Egan DF Shackelford DB Mihaylova MM Gelino S Kohnz RA Mair W Vasquez DS Joshi A Gwinn DM Taylor R Asara JM Fitzpatrick J Dillin A Viollet B Kundu M Hansen M Shaw RJ 2011 Phosphorylation of ULK1 (hATG1) by AMP-activated protein kinase connects energy sensing to mitophagy Science 331 456 461 21205641 PMC3030664
  15. [16]Criollo A Niso-Santano M Malik SA Michaud M Morselli E Marino G Lachkar S Arkhipenko AV Harper F Pierron G Rain JC Ninomiya-Tsuji J Fuentes JM Lavandero S Galluzzi L Maiuri MC Kroemer G 2011 Inhibition of autophagy by TAB2 and TAB3 Embo J 30 4908 4920 22081109 PMC3243630
  16. [17]Nakatogawa H Ichimura Y Ohsumi Y 2007 Atg8, a ubiquitin-like protein required for autophagosome formation, mediates membrane tethering and hemifusion Cell 130 165 178 17632063
  17. [18]Weidberg H Shpilka T Shvets E Abada A Shimron F Elazar Z 2011 LC3 and GATE-16 N termini mediate membrane fusion processes required for autophagosome biogenesis Developmental cell 20 444 454 21497758
  18. [19]Nair U Jotwani A Geng J Gammoh N Richerson D Yen WL Griffith J Nag S Wang K Moss T Baba M McNew JA Jiang X Reggiori F Melia TJ Klionsky DJ 2011 SNARE proteins are required for macroautophagy Cell 146 290 302 21784249 PMC3143362
  19. [22]Gee HY Noh SH Tang BL Kim KH Lee MG 2011 Rescue of DeltaF508-CFTR Trafficking via a GRASP-Dependent Unconventional Secretion Pathway Cell 146 746 760 21884936
  20. [23]Axe EL Walker SA Manifava M Chandra P Roderick HL Habermann A Griffiths G Ktistakis NT 2008 Autophagosome formation from membrane compartments enriched in phosphatidylinositol 3-phosphate and dynamically connected to the endoplasmic reticulum J Cell Biol 182 685 701 18725538 PMC2518708
  21. [24]Ishihara N Hamasaki M Yokota S Suzuki K Kamada Y Kihara A Yoshimori T Noda T Ohsumi Y 2001 Autophagosome requires specific early Sec proteins for its formation and NSF/SNARE for vacuolar fusion Mol Biol Cell 12 3690 3702 11694599 PMC60286
  22. [25]Zoppino FC Militello RD Slavin I Alvarez C Colombo MI 2010 Autophagosome formation depends on the small GTPase Rab1 and functional ER exit sites Traffic 11 1246 1261 20545908
  23. [27]Deretic V 2012 Autophagy as an innate immunity paradigm: expanding the scope and repertoire of pattern recognition receptors Current opinion in immunology 24 21 31 22118953 PMC3288884
  24. [28]Schotman H Karhinen L Rabouille C 2008 dGRASP-mediated noncanonical integrin secretion is required for Drosophila epithelial remodeling Developmental cell 14 171 182 18267086
  25. [29]Barr FA 2005 Purification and functional interactions of GRASP55 with Rab2 Methods Enzymol 403 391 401 16473605
  26. [30]Truschel ST Zhang M Bachert C Macbeth MR Linstedt AD 2012 Allosteric regulation of GRASP protein-dependent Golgi membrane tethering by mitotic phosphorylation The Journal of biological chemistry 287 19870 19875 22523075 PMC3370171
  27. [32]Pilli M Arko-Mensah J Ponpuak M Roberts E Master S Mandell MA Dupont N Ornatowski W Jiang S Bradfute SB Bruun JA Hansen TE Johansen T Deretic V 2012 TBK-1 Promotes Autophagy-Mediated Antimicrobial Defense by Controlling Autophagosome Maturation Immunity 37 223 234 22921120 PMC3428731
  28. [33]Wild P Farhan H McEwan DG Wagner S Rogov VV Brady NR Richter B Korac J Waidmann O Choudhary C Dotsch V Bumann D Dikic I 2011 Phosphorylation of the autophagy receptor optineurin restricts Salmonella growth Science 333 228 233 21617041 PMC3714538
  29. [34]Bjorkoy G Lamark T Brech A Outzen H Perander M Overvatn A Stenmark H Johansen T 2005 p62/SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtin-induced cell death J Cell Biol 171 603 614 16286508 PMC2171557
  30. [35]Matsumoto G Wada K Okuno M Kurosawa M Nukina N 2011 Serine 403 Phosphorylation of p62/SQSTM1 Regulates Selective Autophagic Clearance of Ubiquitinated Proteins Molecular Cell 44 279 289 22017874
  31. [36]Perkins ND 2007 Integrating cell-signalling pathways with NF-kappaB and IKK function Nature reviews Molecular cell biology 8 49 62 17183360
  32. [37]Pfeffer SR 2010 Unconventional secretion by autophagosome exocytosis J Cell Biol 188 451 452 20156968 PMC2828920
  33. [38]Saitoh T Fujita N Jang MH Uematsu S Yang BG Satoh T Omori H Noda T Yamamoto N Komatsu M Tanaka K Kawai T Tsujimura T Takeuchi O Yoshimori T Akira S 2008 Loss of the autophagy protein Atg16L1 enhances endotoxin-induced IL-1beta production Nature 456 264 268 18849965
  34. [40]Nakahira K Haspel JA Rathinam VA Lee SJ Dolinay T Lam HC Englert JA Rabinovitch M Cernadas M Kim HP Fitzgerald KA Ryter SW Choi AM 2011 Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome Nat Immunol 12 222 230 21151103 PMC3079381
  35. [41]Harris J Hartman M Roche C Zeng SG O’Shea A Sharp FA Lambe EM Creagh EM Golenbock DT Tschopp J Kornfeld H Fitzgerald KA Lavelle EC 2011 Autophagy controls IL-1beta secretion by targeting pro-IL-1beta for degradation The Journal of biological chemistry 286 9587 9597 21228274 PMC3058966
  36. [42]Shi CS Shenderov K Huang NN Kabat J Abu-Asab M Fitzgerald KA Sher A Kehrl JH 2012 Activation of autophagy by inflammatory signals limits IL-1beta production by targeting ubiquitinated inflammasomes for destruction Nat Immunol 13 255 263 22286270 PMC4116819
  37. [43]Rubartelli A Cozzolino F Talio M Sitia R 1990 A novel secretory pathway for interleukin-1 beta, a protein lacking a signal sequence Embo J 9 1503 1510 2328723 PMC551842
  38. [45]Dinarello CA 2005 An IL-1 family member requires caspase-1 processing and signals through the ST2 receptor Immunity 23 461 462 16286013
  39. [46]Rathinam VA Vanaja SK Fitzgerald KA 2012 Regulation of inflammasome signaling Nat Immunol 13 333 332 22430786 PMC3523703
  40. [47]Peral de Castro C Jones SA Ni Cheallaigh C Hearnden CA Williams L Winter J Lavelle EC Mills KH Harris J 2012 Autophagy Regulates IL-23 Secretion and Innate T Cell Responses through Effects on IL-1 Secretion J Immunol 189 4144 4153 22972933
  41. [48]Afonina IS Tynan GA Logue SE Cullen SP Bots M Luthi AU Reeves EP McElvaney NG Medema JP Lavelle EC Martin SJ 2011 Granzyme B-dependent proteolysis acts as a switch to enhance the proinflammatory activity of IL-1alpha Molecular cell 44 265 278 22017873 PMC3319689
  42. [49]Yazdi AS Guarda G Riteau N Drexler SK Tardivel A Couillin I Tschopp J 2010 Nanoparticles activate the NLR pyrin domain containing 3 (Nlrp3) inflammasome and cause pulmonary inflammation through release of IL-1alpha and IL-1beta Proc Natl Acad Sci U S A 107 19449 19454 20974980 PMC2984140
  43. [50]Castillo E Dekonenko A Arko-Mensah J Mandell M Dupont N Jiang S Delgado-Vargas M Timmins G Bhattacharya D Yang H Hutt J Lyson C Dobos K Deretic V 2012 Autophagy protects against active tuberculosis by suppressing bacterial burden and inflammation Proc Natl Acad USA In Press PMC3503152 23093667
  44. [52]Gross O Yazdi AS Thomas CJ Masin M Heinz LX Guarda G Quadroni M Drexler SK Tschopp J 2012 Inflammasome activators induce interleukin-1alpha secretion via distinct pathways with differential requirement for the protease function of caspase-1 Immunity 36 388 400 22444631
  45. [53]Schott WH Haskell BD Tse HM Milton MJ Piganelli JD Choisy-Rossi CM Reifsnyder PC Chervonsky AV Leiter EH 2004 Caspase-1 is not required for type 1 diabetes in the NOD mouse Diabetes 53 99 104 14693703
  46. [54]Li Y Arnold JM Pampillo M Babwah AV Peng T 2009 Taurine prevents cardiomyocyte death by inhibiting NADPH oxidase-mediated calpain activation Free radical biology & medicine 46 51 61 18950702
  47. [55]Sharma AK Rohrer B 2007 Sustained elevation of intracellular cGMP causes oxidative stress triggering calpain-mediated apoptosis in photoreceptor degeneration Current eye research 32 259 269 17453946
  48. [56]Tal MC Sasai M Lee HK Yordy B Shadel GS Iwasaki A 2009 Absence of autophagy results in reactive oxygen species-dependent amplification of RLR signaling Proc Natl Acad Sci U S A 106 2770 2775 19196953 PMC2650341
  49. [57]Cadwell K Liu JY Brown SL Miyoshi H Loh J Lennerz JK Kishi C Kc W Carrero JA Hunt S Stone CD Brunt EM Xavier RJ Sleckman BP Li E Mizushima N Stappenbeck TS Virgin HWt 2008 A key role for autophagy and the autophagy gene Atg16l1 in mouse and human intestinal Paneth cells Nature 456 259 263 18849966 PMC2695978
  50. [58]Cadwell K Patel KK Maloney NS Liu TC Ng AC Storer CE Head RD Xavier R Stappenbeck TS Virgin HW 2010 Virus-plus-susceptibility gene interaction determines Crohn’s disease gene Atg16L1 phenotypes in intestine Cell 141 1135 1145 20602997 PMC2908380

Cited by

Sorted by citations

Authors
Jiang, S., Dupont, N., Castillo, E. F., & Deretic, V.
Affiliations
University of New Mexico (US)
ORCID
Venue
Journal of Innate Immunity
Publisher
S. Karger AG
Published
2013
Volume
5
Issue
5
Pages
471-479
ISSN
  • 1662-811X (ISSN-L)
  • 1662-8128
DOI
10.1159/000346707
PMC
PMC3723810
OpenAlex
W1997913020
Cited by
129
References
7
Citations by year
2026: 4 · 2025: 6 · 2024: 7 · 2023: 7 · 2022: 20 · 2021: 10 · 2020: 9 · 2019: 9 · 2018: 12 · 2017: 8 · 2016: 18 · 2015: 7 · 2014: 7 · 2013: 5
FWCI
9.00
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Innate Immunity (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
Funders
  • National Institutes of Health (UL1TR000041)
  • National Institute of Allergy and Infectious Diseases (RC1AI086845, AI069345, R01AI042999, R01AI069345, AI042999, R37AI042999)
  • National Center for Advancing Translational Sciences
Topics
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
  • Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
Keywords
secretory autophagy, unconventional secretion, autophagy, IL-1β, IL-1α, inflammatory cytokines, autophagosomes, inflammatory mediators
MeSH terms
Animals, Autophagy, Cell Communication, Humans, Interleukin-1, Mammals, Inflammation Mediators, Secretory Pathway, Proteolysis

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review