Indoleamine dioxygenase and tryptophan dioxygenase activities are regulated through GAPDH- and Hsp90-dependent control of their heme levels

Biswas, Pranjal; Dai, Yue; Stuehr, Dennis J.

doi:10.1016/j.freeradbiomed.2022.01.008

Cited by 18 publications

(48 citation statements)

References 72 publications

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“…Furthermore, Biswas P. et al have recently demonstrated the biochemical delivery of the intracellular heme to apo-IDO1, describing IDO1 as a heme-protein that can exist naturally, and even predominantly, in its heme-deficient form in the cells. 42 …”

Section: Discussionmentioning

confidence: 99%

The signaling function of IDO1 incites the malignant progression of mouse B16 melanoma

et al. 2023

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Indoleamine 2,3 dioxygenase 1 (IDO1), a leader tryptophan-degrading enzyme, represents a recognized immune checkpoint molecule. In neoplasia, IDO1 is often highly expressed in dendritic cells infiltrating the tumor and/or in tumor cells themselves, particularly in human melanoma. In dendritic cells, IDO1 does not merely metabolize tryptophan into kynurenine but, after phosphorylation of critical tyrosine residues in the non-catalytic small domain, it triggers a signaling pathway prolonging its immunoregulatory effects by a feed-forward mechanism. We here investigated whether the non-enzymatic function of IDO1 could also play a role in tumor cells by using B16-F10 mouse melanoma cells transfected with either the wild-type Ido1 gene ( Ido1 WT ) or a mutated variant lacking the catalytic, but not signaling activity ( Ido1 H350A ). As compared to the Ido1 WT -transfected counterpart (B16 WT ), B16-F10 cells expressing Ido1 H350A (B16 H350A ) were characterized by an in vitro accelerated growth mediated by increased Ras and Erk activities. Faster growth and malignant progression of B16 H350A cells, also detectable in vivo , were found to be accompanied by a reduction in tumor-infiltrating CD8 + T cells and an increase in Foxp3 + regulatory T cells. Our data, therefore, suggest that the IDO1 signaling function can also occur in tumor cells and that alternative therapeutic approach strategies should be undertaken to effectively tackle this important immune checkpoint molecule.

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Section: Discussionmentioning

confidence: 99%

The signaling function of IDO1 incites the malignant progression of mouse B16 melanoma

et al. 2023

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“…In the course of our studies to find a missing factor, we examined GAPDH as it was shown to be a heme-binding protein and acts as a heme chaperone in cells ( 33 , 36 , 37 , 38 , 39 ). In all our previous studies, we have used heme-BSA as the heme donor and failed to see a difference between heme-GAPDH and heme-BSA.…”

Section: Discussionmentioning

confidence: 99%

“…Also in cellular studies, the Stuehr laboratory has shown that Hsp90 binds to the β1 subunit of soluble guanylate cyclase (apo-sGCβ1) to promote heme insertion into apo-sGCβ1, which concurrently associates with a sGCα1 partner subunit to form the mature sGC heterodimer ( 31 , 32 ). The Stuehr laboratory has also shown that Hsp90 is required for heme insertion into indoleamine dioxygenase as well as globins to form mature hemoglobin and myoglobin, which suggests a role for Hsp90 in heme insertion into heme proteins in general ( 33 , 34 ). In both cases of iNOS and guanylate cyclase, Hsp90 was recovered with the apo-enzyme, and very little was found with the mature heme-bound holoenzyme dimer ( 30 , 31 , 32 ).…”

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confidence: 99%

“…For example, Hsp70 is required for cycling of Hsp90 with steroid receptors ( 1 ), but we do not know if it is required for dynamic cycling of Hsp90 with nNOS. In cellular studies, both Hsp90 and the heme donor, GAPDH, have been shown to be needed for insertion of heme into iNOS, indoleamine dioxygenase, guanylate cyclase, hemoglobin, and myoglobin ( 33 , 36 , 37 , 38 , 39 ). In our prior studies with subcellular systems and in cells, heme-bovine serum albumin (BSA) was sufficient to activate apo-nNOS ( 25 , 26 , 27 , 29 ), thus the role of GAPDH as a heme chaperone for nNOS was unclear.…”

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confidence: 99%

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Dynamic cycling with a unique Hsp90/Hsp70-dependent chaperone machinery and GAPDH is needed for heme insertion and activation of neuronal NO synthase

Morishima¹,

Lau²,

Pratt³

et al. 2023

Journal of Biological Chemistry

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“…Samples were again enriched on either sepharose or hemin agarose beads followed by immunoblotting with antibodies to ATP1A-1/2/3, G3BP1, and PHB. GAPDH, which we and others have previously shown interacts with and traffics labile heme 29,36,[49][50][51][52] , was included as a positive control. For each of the three test proteins, strong enrichment was observed with hemin agarose over sepharose, consistent with their high specificity classification by SILAC MS (Figure 4).…”

Section: 4| Validation Of Ms-identified Heme Binding Proteins Visible...mentioning

confidence: 99%

Depletion Assisted Hemin Affinity (DAsHA) Proteomics Reveals an Expanded Landscape of Heme Binding Proteins

Kim

Moore

Mestre-Fos

et al. 2022

Preprint

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Heme b (iron protoporphyrin IX) plays important roles in biology as a metallocofactor and signaling molecule. However, the targets of heme signaling and the network of proteins that mediate the exchange of heme from sites of synthesis or uptake to heme dependent or regulated proteins are poorly understood. Herein, we describe a quantitative mass spectrometry-based chemoproteomics strategy to identify exchange labile hemoproteins in human embryonic kidney HEK293 cells that may be relevant to heme signaling and trafficking. The strategy involves depleting endogenous heme with the heme biosynthetic inhibitor succinylacetone (SA), leaving putative heme binding proteins in their apo-state, followed by the capture of those proteins using hemin-agarose resin and finally elution and identification by mass spectrometry. By identifying only those proteins that interact with high specificity to hemin-agarose relative to control beaded agarose in a SA-dependent manner, we have expanded the number of proteins and ontologies that may be involved in binding and buffering labile heme or are targets of heme signaling. Notably, these include proteins involved in chromatin remodeling, DNA damage response, RNA splicing, cytoskeletal organization and vesicular trafficking, many of which have been associated with heme through complimentary studies published recently. Taken together, these results provide support for the emerging role for heme in an expanded set of cellular processes from genome integrity to protein trafficking and beyond.

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Indoleamine dioxygenase and tryptophan dioxygenase activities are regulated through GAPDH- and Hsp90-dependent control of their heme levels

Cited by 18 publications

References 72 publications

The signaling function of IDO1 incites the malignant progression of mouse B16 melanoma

The signaling function of IDO1 incites the malignant progression of mouse B16 melanoma

Dynamic cycling with a unique Hsp90/Hsp70-dependent chaperone machinery and GAPDH is needed for heme insertion and activation of neuronal NO synthase

Depletion Assisted Hemin Affinity (DAsHA) Proteomics Reveals an Expanded Landscape of Heme Binding Proteins

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