<i>Shigella</i>effector IpaH4.5 targets 19S regulatory particle subunit RPN13 in the 26S proteasome to dampen cytotoxic T lymphocyte activation

Otsubo, Ryota; Mimuro, Hitomi; Ashida, Hiroshi; Hamazaki, Jun; Murata, Shigeo; Sasakawa, Chihiro

doi:10.1111/cmi.12974

Cited by 13 publications

(11 citation statements)

References 33 publications

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“…RPN11 inhibitor capzimin [44] and RPT4-binding peptoid RIP-1 were also identified [45] but their activity in vivo is not known. In addition to our molecular series [11,14,15], RPN13 has been targeted with siRNA [12], diphenyldihaloketones CLEFMA and EF24 [46], peptoid approaches [47], thalidomidebased degrader WL40 [48] and, interestingly, Shigella flexneri invasion plasmid antigen H (IpaH) 4.5 is a E3 ubiquitin ligase that induces RPN13 degradation via the proteasome and enhances bacterial pathogenicity [49]. However, identifying 19S RP inhibitors with drug-like properties remains challenging and to date only VLX-1570 has been tested clinically [7].…”

Section: Discussionmentioning

confidence: 99%

Chirality and asymmetry increase the potency of candidate ADRM1/RPN13 inhibitors

et al. 2021

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Bortezomib and the other licensed 20S proteasome inhibitors show robust activity against liquid tumors like multiple myeloma, but have disappointed against solid tumors including ovarian cancer. Consequently, interest is mounting in alternative non-peptide based drugs targeting the proteasome’s 19S regulatory particle subunit, including its ubiquitin receptor RPN13. RA183 and RA375 are more potent analogs of the prototypic inhibitor of RPN13 (iRPN13) called RA190, and they show promise for the treatment of ovarian cancer. Here we demonstrate that rendering these candidate RPN13 inhibitors chiral and asymmetric through the addition of a single methyl to the core piperidone moiety increases their potency against cancer cell lines, with the S-isomer being more active than the R-isomer. The enhanced cancer cell cytotoxicities of these compounds are associated with improved binding to RPN13 in cell lysates, ATP depletion by inhibition of glycolysis and mitochondrial electron chain transport, mitochondrial depolarization and perinuclear clustering, oxidative stress and glutathione depletion, and rapid accumulation of high molecular weight polyubiquitinated proteins with a consequent unresolved ubiquitin proteasome system (UPS) stress response. Cytotoxicity was associated with an early biomarker of apoptosis, increased surface annexin V binding. As for cisplatin, BRCA2 and ATM deficiency conferred increased sensitivity to these iRPN13s. Ubiquitination plays an important role in coordinating DNA damage repair and the iRPN13s may compromise this process by depletion of monomeric ubiquitin following its sequestration in high molecular weight polyubiquitinated protein aggregates. Indeed, a synergistic cytotoxic response was evident upon treatment of several ovarian cancer cell lines with either cisplatin or doxorubicin and our new candidate iRPN13s, suggesting that such a combination approach warrants further exploration for the treatment of ovarian cancer.

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Section: Discussionmentioning

confidence: 99%

Chirality and asymmetry increase the potency of candidate ADRM1/RPN13 inhibitors

et al. 2021

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“…Through E3 ubiquitin ligase activities, IpaH4.5 targets and degrades RPN13 results by inhibiting 26S proteasome activities. This outcome leads to the suppression of proteasome-catalyzed peptide and reduction of cross-presentation to CD8+ cell [ 165 ].…”

Section: Introductionmentioning

confidence: 99%

Molecular mechanisms of Shigella effector proteins: a common pathogen among diarrheic pediatric population

et al. 2022

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Different gastrointestinal pathogens cause diarrhea which is a very common problem in children aged under 5 years. Among bacterial pathogens, Shigella is one of the main causes of diarrhea among children, and it accounts for approximately 11% of all deaths among children aged under 5 years. The case-fatality rates for Shigella among the infants and children aged 1 to 4 years are 13.9% and 9.4%, respectively. Shigella uses unique effector proteins to modulate intracellular pathways. Shigella cannot invade epithelial cells on the apical site; therefore, it needs to pass epithelium through other cells rather than the epithelial cell. After passing epithelium, macrophage swallows Shigella, and the latter should prepare itself to exhibit at least two types of responses: (I) escaping phagocyte and (II) mediating invasion of and injury to the recurrent PMN. The presence of PMN and invitation to a greater degree resulted in gut membrane injuries and greater bacterial penetration. Infiltration of Shigella to the basolateral space mediates (A) cell attachment, (B) cell entry, (C) evasion of autophagy recognition, (D) vacuole formation and and vacuole rapture, (E) intracellular life, (F) Shiga toxin, and (G) immune response. In this review, an attempt is made to explain the role of each factor in Shigella infection.

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“…Inhibition of antigen presentation . Pertussis toxin from Bordetella ( 80 ), EsxG, EsxH ( 244 ), Vpu from HIV-1 ( 245 ), ORF66 from HHV-3 ( 246 ), BILF1 ( 247 , 248 ), BNLF2a ( 249 – 251 ), and BZLF1 from HHV-4 ( 252 ), E1A and E3 from human adenovirus ( 253 , 254 ), LpqH ( 255 , 256 ), LprA ( 257 ), LprG ( 258 ), and PPE38 ( 259 ) from M. tuberculosis , SteD from Salmonella ( 260 ), and IpaH4.5 from Shigella ( 261 ) inhibit host antigen presentation by various mechanisms.…”

Section: Identifying and Assessing Sequences Of Concernmentioning

confidence: 99%

Categorizing Sequences of Concern by Function To Better Assess Mechanisms of Microbial Pathogenesis

et al. 2022

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To identify sequences with a role in microbial pathogenesis, we assessed the adequacy of their annotation by existing controlled vocabularies and sequence databases. Our goal was to regularize descriptions of microbial pathogenesis for improved integration with bioinformatic applications. Here we review the challenges of annotating sequences for pathogenic activity. We relate the categorization of more than 2750 sequences of pathogenic microbes through a controlled vocabulary called Functions of Sequences of Concern (FunSoCs). These allow for an ease of description by both humans and machines. We provide a subset of 220 fully annotated sequences in the supplementary material as examples. The use of this compact (∼30 terms) controlled vocabulary has potential benefits for research in microbial genomics, public health, biosecurity, biosurveillance, and the characterization of new and emerging pathogens.

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Shigellaeffector IpaH4.5 targets 19S regulatory particle subunit RPN13 in the 26S proteasome to dampen cytotoxic T lymphocyte activation

Cited by 13 publications

References 33 publications

Chirality and asymmetry increase the potency of candidate ADRM1/RPN13 inhibitors

Chirality and asymmetry increase the potency of candidate ADRM1/RPN13 inhibitors

Molecular mechanisms of Shigella effector proteins: a common pathogen among diarrheic pediatric population

Categorizing Sequences of Concern by Function To Better Assess Mechanisms of Microbial Pathogenesis

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