Multi-layered control of Galectin-8 mediated autophagy during adenovirus cell entry through a conserved PPxY motif in the viral capsid

Montespan, Charlotte; Marvin, Shauna A.; Austin, Sisley; Burrage, Andrew M.; Roger, Benoît; Rayne, Fabienne; Faure, Muriel; Campell, Edward M.; Schneider, Carola; Reimer, Rudolph; Grünewald, Kay; Wiethoff, Christopher M.; Wodrich, Harald

doi:10.1371/journal.ppat.1006217

Cited by 63 publications

(115 citation statements)

References 63 publications

(88 reference statements)

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“…Concentrations. A characteristic feature of damaged endosomes (20)(21)(22)(23)(24)(25)(26) is the presence of cytosolic β-galactosides that are ordinarily found on the luminal side of endolysosomal compartments (27).…”

Section: Cpmps and Cpps Do Not Induce Gal Recruitment At Submicromolarmentioning

confidence: 99%

“…In particular, Gal3 and Gal8 are recruited to damaged Rab7 + and Lamp1 + endosomes that form along the degradative branch of the endocytic pathway (20,31). Previous work has shown that endosomal damage can be detected by monitoring the translocation of eGFP fusions of Gal3 or Gal8 from the cytosol to endosome surfaces (20)(21)(22)(23)(24)(25)(26). However, the effects of CPPs or CPMPs on the extent of Gal-recruitment to potentially damaged endosomes have not previously been studied.…”

Section: Cpmps and Cpps Do Not Induce Gal Recruitment At Submicromolarmentioning

confidence: 99%

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HOPS-dependent endosomal fusion required for efficient cytosolic delivery of therapeutic peptides and small proteins

Steinauer

LaRochelle

Knox

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Protein therapeutics represent a significant and growing component of the modern pharmacopeia, but their potential to treat human disease is limited because most proteins fail to traffic across biological membranes. Recently, we discovered a class of cell-permeant miniature proteins (CPMPs) containing a precisely defined, penta-arginine (penta-Arg) motif that traffics readily to the cytosol and nucleus of mammalian cells with efficiencies that rival those of hydrocarbon-stapled peptides active in animals and man. Like many cell-penetrating peptides (CPPs), CPMPs enter the endocytic pathway; the difference is that CPMPs containing a penta-Arg motif are released efficiently from endosomes, while other CPPs are not. Here, we seek to understand how CPMPs traffic from endosomes into the cytosol and what factors contribute to the efficiency of endosomal release. First, using two complementary cellbased assays, we exclude endosomal rupture as the primary means of endosomal escape. Next, using an RNA interference screen, fluorescence correlation spectroscopy, and confocal imaging, we identify VPS39-a gene encoding a subunit of the homotypic fusion and protein-sorting (HOPS) complex-as a critical determinant in the trafficking of CPMPs and hydrocarbon-stapled peptides to the cytosol. Although CPMPs neither inhibit nor activate HOPS function, HOPS activity is essential to efficiently deliver CPMPs to the cytosol. CPMPs localize within the lumen of Rab7 + and Lamp1 + endosomes and their transport requires HOPS activity. Overall, our results identify Lamp1 + late endosomes and lysosomes as portals for passing proteins into the cytosol and suggest that this environment is prerequisite for endosomal escape.cell-penetrating peptides | peptidomimetics | enzyme replacement therapy | endocytosis | protein therapeutics

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Section: Cpmps and Cpps Do Not Induce Gal Recruitment At Submicromolarmentioning

confidence: 99%

Section: Cpmps and Cpps Do Not Induce Gal Recruitment At Submicromolarmentioning

confidence: 99%

HOPS-dependent endosomal fusion required for efficient cytosolic delivery of therapeutic peptides and small proteins

Steinauer

LaRochelle

Knox

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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“…It can serve dual roles in virus infection with either pro- or anti-viral functions depending on the virus and the stage of the viral replication cycle [37]. It not only is required for an antiviral response against some virus infection [38], but also take an active part in the viral life cycle by, eg, facilitating its entry into and release from cells [39]. In PEDV-infected cells, autophagy is often hijacked by viruses and manipulated to their own advantage [22].…”

Section: Discussionmentioning

confidence: 99%

Deoxynivalenol Promotes Porcine Epidemic Diarrhea Virus Infection and Aggravates Gut Barrier Injury

Wang

et al. 2019

Preprint

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23Porcine epidemic diarrhea virus (PEDV) is a highly contagious pathogenic virus that 24 causes severe diarrhea and dehydration in pigs of all ages. Deoxynivalenol (DON), the 25 most abundant trichothecene in food and feed, causes vomit and diarrhea in animals 26 and human. However, whether DON exposure could affect PEDV infection remains 27 unknown. Herein, we investigated the impacts of DON on entry and replication of 28 PEDV, morbidity situation of piglets and the mechanisms involved. In vivo, twenty-29 seven piglets infected naturally with PEDV were randomly divided into three groups, 30 receiving the basal diet containing 0, 750 and 1500 μg/kg DON, respectively. We 31 observed significant increases in the diarrhea rates, the villous injury of jejunums and 32 the PEDV proliferation of duodenum, jejunum, ileum and mesenterium of piglets in 33 experimental groups compared with control. Additionally, the autophagosome-like 34 vesicles and the autophagy-related protein expressions were also increased in 35 experimental groups. In vitro, we observed that, approximately 2 hrs post-infection, 36 0.1, 0.5 and 1.0 μM DON promoted PEDV entry (P < 0.05) in IPEC-J2s and resulted 37 in tight junction protein occludin internalization. Knockdown of occludin and 38 CRISPR-Cas9-mediated knockout of LC3B indicated a vital role of autophagy-induced 39 occludin internalization in DON-promoted PEDV entry. We also observed that, 24 hrs 40 post-infection, a significant increase in PEDV replication after 0.1, 0.5 and 1.0 μM 41 DON treatment, along with the induction of a complete autophagy. Specifically, 42 deletion of LC3B indicated a crucial role of autophagy in DON-promoted PEDV . CC-BY 4.0 International license author/funder. It is made available under aThe copyright holder for this preprint (which was not peer-reviewed) is the . https://doi.org/10.1101/852608 doi: bioRxiv preprint 3 43 replication. Pretreatment with SB202190, a p38 signaling inhibitor, abolished the 44 induction of autophagy. Furthermore, downregulation of type I interferon revealed that 45 DON contributed PEDV to escape innate immune. Mechanistically, DON-caused 46 innate immune escape was related to the upregulation of LC3B, which further inhibited 47 STING phosphorylation. Taken together, DON could promote PEDV infection by 48 inducing occludin internalization and innate immune escape via triggering p38-49 mediated autophagy.50 Author summary 53 Porcine epidemic diarrhea (PED), a devastating enteric disease, leads to catastrophic 54 economic loss to the global pig industry. Its primary pathogen is the coronavirus PED 55 virus (PEDV). Growing evidence indicates that pathogen infection is not the only factor 56 of PED outbreaks, other non-infectious factors is also related to this disease. We 57 guessed some ubiquitous substances, such as deoxynivalenol (DON), that lead to pig 58 intestinal epithelial cell stress might encourage the progress and spread of PED. In the 59 present study, the weaning piglets infected naturally with PEDV and the IPEC-J2 cell 60 lin...

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“…2B) (124). Later findings by the same group suggested that recruitment of Nedd4 by the PPxY motif of PVI was a strategy used by the virus to divert the host E3 ubiquitin ligase from its physiological function in regulating autophagy, thus allowing the virus to evade the host autophagic response (125,126). Indeed, the authors observed that the WT PPxY motif of PVI prevented efficient formation of autolysosomes, and they speculated that the WT virus may interfere with elongation of the autophagosomal membrane, thereby preventing autophagosome formation (125,126).…”

Section: Modular Interactions and Virus Entry/replicationmentioning

confidence: 99%

Viruses go modular

Shepley-McTaggart

Fan

Sudol

et al. 2020

Journal of Biological Chemistry

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The WW domain is a modular protein structure that recognizes the proline-rich Pro-Pro-x-Tyr (PPxY) motif contained in specific target proteins. The compact modular nature of the WW domain makes it ideal for mediating interactions between proteins in complex networks and signaling pathways of the cell (e.g. the Hippo pathway). As a result, WW domains play key roles in a plethora of both normal and disease processes. Intriguingly, RNA and DNA viruses have evolved strategies to hijack cellular WW domain-containing proteins and thereby exploit the modular functions of these host proteins for various steps of the virus life cycle, including entry, replication, and egress. In this review, we summarize key findings in this rapidly expanding field, in which new virus-host interactions continue to be identified. Further unraveling of the molecular aspects of these crucial virus-host interactions will continue to enhance our fundamental understanding of the biology and pathogenesis of these viruses. We anticipate that additional insights into these interactions will help support strategies to develop a new class of small-molecule inhibitors of viral PPxY-host WW-domain interactions that could be used as antiviral therapeutics. . 2 The abbreviations used are: PPxY, proline-proline-x-tyrosine motif; AdV, adenovirus; ART protein, arrestin-related trafficking protein; BAG3, BCL2associated athanogene 3; BUL1 and -2, binds ubiquitin ligase proteins 1 and 2; CASA, chaperone-assisted selective autophagy; CIRF, cell-intrinsic restriction factor; EBV, Epstein-Barr virus; EBOV, Ebola virus; ESCRT, endosomal sorting complex required for transport; HECT, homologous to the E6AP carboxyl terminus (E3 ligase family); HHV, human herpes virus; HTLV-1, human T-cell leukemia virus 1; IFITM3, interferon-induced transmembrane protein 3; ISG15, interferon stimulated gene 15; ITCH (AIP4), Itchy E3 ubiquitin protein ligase; LDI-1 and -2, late domain-interacting proteins 1 and 2; L domain, viral late domain; LMP2A, latent membrane protein 2A; MARV, Marburg virus; MLV, murine leukemia virus; Nedd4, neuronal precursor cell-expressed developmentally down-regulated 4; PVI, preprotein VI (membrane lytic internal capsid protein); Rsp5, yeast reverses SPTphenotype protein 5 (E3 ubiquitin-protein ligase); RSV, Rous sarcoma virus; SMURF1 and -2, Smad ubiquitin-regulating factors 1 and 2; TBSV, tomato bushy stunt virus; Tsg101, tumor susceptibility gene 101; VLP, virus-like particle; VSV, vesicular stomatitis virus; WOX1, WW domain-containing oxidoreductase; WWP1 and -2, WW domain-containing E3 ubiquitin protein ligase 1 and 2; MS, multiple sclerosis. cro REVIEWS 4604

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Multi-layered control of Galectin-8 mediated autophagy during adenovirus cell entry through a conserved PPxY motif in the viral capsid

Cited by 63 publications

References 63 publications

HOPS-dependent endosomal fusion required for efficient cytosolic delivery of therapeutic peptides and small proteins

HOPS-dependent endosomal fusion required for efficient cytosolic delivery of therapeutic peptides and small proteins

Deoxynivalenol Promotes Porcine Epidemic Diarrhea Virus Infection and Aggravates Gut Barrier Injury

Viruses go modular

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