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Article ; Online: Lysosomal lipid peroxidation regulates tumor immunity.

Bhardwaj, Monika / Lee, Jennifer J / Versace, Amanda M / Harper, Sandra L / Goldman, Aaron R / Crissey, Mary Ann S / Jain, Vaibhav / Singh, Mahendra Pal / Vernon, Megane / Aplin, Andrew E / Lee, Seokwoo / Morita, Masao / Winkler, Jeffrey D / Liu, Qin / Speicher, David W / Amaravadi, Ravi K

The Journal of clinical investigation

2023 Volume 133, Issue 8

Abstract: Lysosomal inhibition elicited by palmitoyl-protein thioesterase 1 (PPT1) inhibitors such as DC661 can produce cell death, but the mechanism for this is not completely understood. Programmed cell death pathways (autophagy, apoptosis, necroptosis, ... ...

Abstract	Lysosomal inhibition elicited by palmitoyl-protein thioesterase 1 (PPT1) inhibitors such as DC661 can produce cell death, but the mechanism for this is not completely understood. Programmed cell death pathways (autophagy, apoptosis, necroptosis, ferroptosis, and pyroptosis) were not required to achieve the cytotoxic effect of DC661. Inhibition of cathepsins, or iron or calcium chelation, did not rescue DC661-induced cytotoxicity. PPT1 inhibition induced lysosomal lipid peroxidation (LLP), which led to lysosomal membrane permeabilization and cell death that could be reversed by the antioxidant N-acetylcysteine (NAC) but not by other lipid peroxidation antioxidants. The lysosomal cysteine transporter MFSD12 was required for intralysosomal transport of NAC and rescue of LLP. PPT1 inhibition produced cell-intrinsic immunogenicity with surface expression of calreticulin that could only be reversed with NAC. DC661-treated cells primed naive T cells and enhanced T cell-mediated toxicity. Mice vaccinated with DC661-treated cells engendered adaptive immunity and tumor rejection in "immune hot" tumors but not in "immune cold" tumors. These findings demonstrate that LLP drives lysosomal cell death, a unique immunogenic form of cell death, pointing the way to rational combinations of immunotherapy and lysosomal inhibition that can be tested in clinical trials.
MeSH term(s)	Mice ; Animals ; Lipid Peroxidation ; Apoptosis ; Cell Death ; Neoplasms/pathology ; Antioxidants/pharmacology ; Lysosomes/metabolism
Chemical Substances	Antioxidants
Language	English
Publishing date	2023-04-17
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	3067-3
ISSN	1558-8238 ; 0021-9738
ISSN (online)	1558-8238
ISSN	0021-9738
DOI	10.1172/JCI164596
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Article ; Online: Targeting UGCG Overcomes Resistance to Lysosomal Autophagy Inhibition.

Jain, Vaibhav / Harper, Sandra L / Versace, Amanda M / Fingerman, Dylan / Brown, Gregory Schuyler / Bhardwaj, Monika / Crissey, Mary Ann S / Goldman, Aaron R / Ruthel, Gordon / Liu, Qin / Zivkovic, Aleksandra / Stark, Holgar / Herlyn, Meenhard / Gimotty, Phyllis A / Speicher, David W / Amaravadi, Ravi K

Cancer discovery

2022 Volume 13, Issue 2, Page(s) 454–473

Abstract: Lysosomal autophagy inhibition (LAI) with hydroxychloroquine or DC661 can enhance cancer therapy, but tumor regrowth is common. To elucidate LAI resistance, proteomics and immunoblotting demonstrated that LAI induced lipid metabolism enzymes in multiple ... ...

Abstract	Lysosomal autophagy inhibition (LAI) with hydroxychloroquine or DC661 can enhance cancer therapy, but tumor regrowth is common. To elucidate LAI resistance, proteomics and immunoblotting demonstrated that LAI induced lipid metabolism enzymes in multiple cancer cell lines. Lipidomics showed that LAI increased cholesterol, sphingolipids, and glycosphingolipids. These changes were associated with striking levels of GM1+ membrane microdomains (GMM) in plasma membranes and lysosomes. Inhibition of cholesterol/sphingolipid metabolism proteins enhanced LAI cytotoxicity. Targeting UDP-glucose ceramide glucosyltransferase (UGCG) synergistically augmented LAI cytotoxicity. Although UGCG inhibition decreased LAI-induced GMM and augmented cell death, UGCG overexpression led to LAI resistance. Melanoma patients with high UGCG expression had significantly shorter disease-specific survival. The FDA-approved UGCG inhibitor eliglustat combined with LAI significantly inhibited tumor growth and improved survival in syngeneic tumors and a therapy-resistant patient-derived xenograft. These findings nominate UGCG as a new cancer target, and clinical trials testing UGCG inhibition in combination with LAI are warranted. Significance: We discovered UGCG-dependent lipid remodeling drives resistance to LAI. Targeting UGCG with a drug approved for a lysosomal storage disorder enhanced LAI antitumor activity without toxicity. LAI and UGCG inhibition could be tested clinically in multiple cancers. This article is highlighted in the In This Issue feature, p. 247.
MeSH term(s)	Humans ; Neoplasms ; Autophagy ; Lysosomes ; Cholesterol
Chemical Substances	ceramide glucosyltransferase (EC 2.4.1.80) ; Cholesterol (97C5T2UQ7J)
Language	English
Publishing date	2022-11-09
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2625242-9
ISSN	2159-8290 ; 2159-8274
ISSN (online)	2159-8290
ISSN	2159-8274
DOI	10.1158/2159-8290.CD-22-0535
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Article ; Online: Full-Length Anion Exchanger 1 Structure and Interactions with Ankyrin-1 Determined by Zero Length Crosslinking of Erythrocyte Membranes.

Rivera-Santiago, Roland / Harper, Sandra L / Sriswasdi, Sira / Hembach, Peter / Speicher, David W

Structure (London, England : 1993)

2017 Volume 25, Issue 1, Page(s) 132–145

Abstract: Anion exchanger 1 (AE1) is a critical transporter and the primary structural scaffold for large macromolecular complexes responsible for erythrocyte membrane flexibility and integrity. We used zero-length crosslinking and mass spectrometry to probe AE1 ... ...

Abstract	Anion exchanger 1 (AE1) is a critical transporter and the primary structural scaffold for large macromolecular complexes responsible for erythrocyte membrane flexibility and integrity. We used zero-length crosslinking and mass spectrometry to probe AE1 structures and interactions in intact erythrocyte membranes. An experimentally verified full-length model of AE1 dimers was developed by combining crosslink-defined distance constraints with homology modeling. Previously unresolved cytoplasmic loops in the AE1 C-terminal domain are packed at the domain-domain interface on the cytoplasmic face of the membrane where they anchor the N-terminal domain's location and prevent it from occluding the ion channel. Crosslinks between AE1 dimers and ankyrin-1 indicate the likely topology for AE1 tetramers and suggest that ankyrin-1 wraps around AE1 tetramers, which may stabilize this oligomer state. This interaction and interactions of AE1 with other major erythrocyte membrane proteins show that protein-protein contacts are often substantially more extensive than previously reported.
MeSH term(s)	Anion Exchange Protein 1, Erythrocyte/chemistry ; Anion Exchange Protein 1, Erythrocyte/genetics ; Anion Exchange Protein 1, Erythrocyte/metabolism ; Ankyrins/metabolism ; Cross-Linking Reagents ; Erythrocyte Membrane/metabolism ; Humans ; Mass Spectrometry ; Models, Molecular ; Protein Binding ; Protein Conformation ; Protein Domains ; Protein Multimerization ; Structural Homology, Protein
Chemical Substances	ANK1 protein, human ; Anion Exchange Protein 1, Erythrocyte ; Ankyrins ; Cross-Linking Reagents ; SLC4A1 protein, human
Language	English
Publishing date	2017-01-03
Publishing country	United States
Document type	Journal Article
ZDB-ID	1213087-4
ISSN	1878-4186 ; 0969-2126
ISSN (online)	1878-4186
ISSN	0969-2126
DOI	10.1016/j.str.2016.11.017
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Article ; Online: Enhanced identification of zero-length chemical cross-links using label-free quantitation and high-resolution fragment ion spectra.

Sriswasdi, Sira / Harper, Sandra L / Tang, Hsin-Yao / Speicher, David W

Journal of proteome research

2014 Volume 13, Issue 2, Page(s) 898–914

Abstract: Chemical cross-linking coupled to mass spectrometry provides structural information that is useful for probing protein conformations and providing experimental support for molecular models. "Zero-length" cross-links have greater value for these ... ...

Abstract	Chemical cross-linking coupled to mass spectrometry provides structural information that is useful for probing protein conformations and providing experimental support for molecular models. "Zero-length" cross-links have greater value for these applications than longer cross-links because they provide more stringent distance constraints. However, this method is less commonly utilized because it cannot take advantage of isotopic labels, MS-labile bonds, or enrichment tags to facilitate identification. In this study, we combined label-free precursor ion quantitation and targeted tandem mass spectrometry with a new software tool, Zero-length Cross-link Miner (ZXMiner), to form a multitiered analysis strategy. A major, critical objective was to simultaneously achieve very high accuracy with essentially no false-positive cross-link identifications while maintaining a good depth of analysis. Our strategy was optimized on several proteins with known crystal structures. Comparison of ZXMiner to several existing cross-link analysis software showed that other algorithms detected less true positive cross-links and were far less accurate. Although prior use of zero-length cross-linking was typically restricted to small proteins, ZXMiner and the associated strategy enable facile analysis of very large protein complexes. This was demonstrated by identification of zero-length cross-links using purified 526 kDa spectrin heterodimers and intact red cell membranes and membrane skeletons.
MeSH term(s)	Chromatography, Liquid ; Cross-Linking Reagents/chemistry ; Erythrocyte Membrane/chemistry ; Glutathione Transferase/chemistry ; Humans ; Myoglobin/chemistry ; Protein Conformation ; Tandem Mass Spectrometry
Chemical Substances	Cross-Linking Reagents ; Myoglobin ; Glutathione Transferase (EC 2.5.1.18)
Language	English
Publishing date	2014-01-07
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2078618-9
ISSN	1535-3907 ; 1535-3893
ISSN (online)	1535-3907
ISSN	1535-3893
DOI	10.1021/pr400953w
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Article: Enhanced Identification of Zero-Length Chemical Cross-Links Using Label-Free Quantitation and High-Resolution Fragment Ion Spectra

Sriswasdi, Sira / Harper, Sandra L / Tang, Hsin-Yao / Speicher, David W

Journal of Proteome Research. 2014 Feb. 07, v. 13, no. 2

2014

Abstract: Chemical cross-linking coupled to mass spectrometry provides structural information that is useful for probing protein conformations and providing experimental support for molecular models. “Zero-length” cross-links have greater value for these ... ...

Abstract	Chemical cross-linking coupled to mass spectrometry provides structural information that is useful for probing protein conformations and providing experimental support for molecular models. “Zero-length” cross-links have greater value for these applications than longer cross-links because they provide more stringent distance constraints. However, this method is less commonly utilized because it cannot take advantage of isotopic labels, MS-labile bonds, or enrichment tags to facilitate identification. In this study, we combined label-free precursor ion quantitation and targeted tandem mass spectrometry with a new software tool, Zero-length Cross-link Miner (ZXMiner), to form a multitiered analysis strategy. A major, critical objective was to simultaneously achieve very high accuracy with essentially no false-positive cross-link identifications while maintaining a good depth of analysis. Our strategy was optimized on several proteins with known crystal structures. Comparison of ZXMiner to several existing cross-link analysis software showed that other algorithms detected less true positive cross-links and were far less accurate. Although prior use of zero-length cross-linking was typically restricted to small proteins, ZXMiner and the associated strategy enable facile analysis of very large protein complexes. This was demonstrated by identification of zero-length cross-links using purified 526 kDa spectrin heterodimers and intact red cell membranes and membrane skeletons.
Keywords	algorithms ; cell membranes ; computer software ; crosslinking ; crystal structure ; molecular models ; proteome ; spectrin ; tandem mass spectrometry
Language	English
Dates of publication	2014-0207
Size	p. 898-914.
Publishing place	American Chemical Society
Document type	Article
ZDB-ID	2078618-9
ISSN	1535-3907 ; 1535-3893
ISSN (online)	1535-3907
ISSN	1535-3893
DOI	10.1021%2Fpr400953w
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Article ; Online: PPT1 inhibition enhances the antitumor activity of anti-PD-1 antibody in melanoma.

JCI insight

2022 Volume 7, Issue 20

MeSH term(s)	Humans ; Melanoma ; Programmed Cell Death 1 Receptor ; Membrane Proteins ; Thiolester Hydrolases
Chemical Substances	Programmed Cell Death 1 Receptor ; PPT1 protein, human (EC 3.1.2.22) ; Membrane Proteins ; Thiolester Hydrolases (EC 3.1.2.-)
Language	English
Publishing date	2022-10-24
Publishing country	United States
Document type	Journal Article ; Published Erratum
ISSN	2379-3708
ISSN (online)	2379-3708
DOI	10.1172/jci.insight.165688
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Article ; Online: Probing structures of large protein complexes using zero-length cross-linking.

Rivera-Santiago, Roland F / Sriswasdi, Sira / Harper, Sandra L / Speicher, David W

Methods (San Diego, Calif.)

2015 Volume 89, Page(s) 99–111

Abstract: Structural mass spectrometry (MS) is a field with growing applicability for addressing complex biophysical questions regarding proteins and protein complexes. One of the major structural MS approaches involves the use of chemical cross-linking coupled ... ...

Abstract	Structural mass spectrometry (MS) is a field with growing applicability for addressing complex biophysical questions regarding proteins and protein complexes. One of the major structural MS approaches involves the use of chemical cross-linking coupled with MS analysis (CX-MS) to identify proximal sites within macromolecules. Identified cross-linked sites can be used to probe novel protein-protein interactions or the derived distance constraints can be used to verify and refine molecular models. This review focuses on recent advances of "zero-length" cross-linking. Zero-length cross-linking reagents do not add any atoms to the cross-linked species due to the lack of a spacer arm. This provides a major advantage in the form of providing more precise distance constraints as the cross-linkable groups must be within salt bridge distances in order to react. However, identification of cross-linked peptides using these reagents presents unique challenges. We discuss recent efforts by our group to minimize these challenges by using multiple cycles of LC-MS/MS analysis and software specifically developed and optimized for identification of zero-length cross-linked peptides. Representative data utilizing our current protocol are presented and discussed.
MeSH term(s)	Animals ; Chromatography, Liquid/methods ; Cross-Linking Reagents/chemistry ; Humans ; Macromolecular Substances/analysis ; Macromolecular Substances/chemistry ; Protein Conformation ; Tandem Mass Spectrometry/methods
Chemical Substances	Cross-Linking Reagents ; Macromolecular Substances
Language	English
Publishing date	2015-05-01
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1066584-5
ISSN	1095-9130 ; 1046-2023
ISSN (online)	1095-9130
ISSN	1046-2023
DOI	10.1016/j.ymeth.2015.04.031
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Zs.A 3239: Show issues

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Article ; Online: Probing large conformational rearrangements in wild-type and mutant spectrin using structural mass spectrometry.

Sriswasdi, Sira / Harper, Sandra L / Tang, Hsin-Yao / Gallagher, Patrick G / Speicher, David W

Proceedings of the National Academy of Sciences of the United States of America

2014 Volume 111, Issue 5, Page(s) 1801–1806

Abstract: Conformational changes of macromolecular complexes play key mechanistic roles in many biological processes, but large, highly flexible proteins and protein complexes usually cannot be analyzed by crystallography or NMR. Here, structures and ... ...

Abstract	Conformational changes of macromolecular complexes play key mechanistic roles in many biological processes, but large, highly flexible proteins and protein complexes usually cannot be analyzed by crystallography or NMR. Here, structures and conformational changes of the highly flexible, dynamic red cell spectrin and effects of a common mutation that disrupts red cell membranes were elucidated using chemical cross-linking coupled with mass spectrometry. Interconversion of spectrin between closed dimers, open dimers, and tetramers plays a key role in maintaining red cell shape and membrane integrity, and spectrins in other cell types serve these as well as more diverse functions. Using a minispectrin construct, experimentally verified structures of closed dimers and tetramers were determined by combining distance constraints from zero-length cross-links with molecular models and biophysical data. Subsequent biophysical and structural mass spectrometry characterization of a common hereditary elliptocytosis-related mutation of α-spectrin, L207P, showed that cell membranes were destabilized by a shift of the dimer-tetramer equilibrium toward closed dimers. The structure of αL207P mutant closed dimers provided previously unidentified mechanistic insight into how this mutation, which is located a large distance from the tetramerization site, destabilizes spectrin tetramers and cell membrane integrity.
MeSH term(s)	Biophysical Phenomena ; Mass Spectrometry/methods ; Mutant Proteins/chemistry ; Protein Multimerization ; Protein Structure, Quaternary ; Spectrin/chemistry
Chemical Substances	Mutant Proteins ; Spectrin (12634-43-4)
Language	English
Publishing date	2014-01-22
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.1317620111
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Zs.A 1148: Show issues

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Article ; Online: The common hereditary elliptocytosis-associated α-spectrin L260P mutation perturbs erythrocyte membranes by stabilizing spectrin in the closed dimer conformation.

Harper, Sandra L / Sriswasdi, Sira / Tang, Hsin-Yao / Gaetani, Massimiliano / Gallagher, Patrick G / Speicher, David W

Blood

2013 Volume 122, Issue 17, Page(s) 3045–3053

Abstract: Hereditary elliptocytosis (HE) and hereditary pyropoikilocytosis (HPP) are common disorders of erythrocyte shape primarily because of mutations in spectrin. The most common HE/HPP mutations are located distant from the critical αβ-spectrin ... ...

Abstract	Hereditary elliptocytosis (HE) and hereditary pyropoikilocytosis (HPP) are common disorders of erythrocyte shape primarily because of mutations in spectrin. The most common HE/HPP mutations are located distant from the critical αβ-spectrin tetramerization site, yet still interfere with formation of spectrin tetramers and destabilize the membrane by unknown mechanisms. To address this question, we studied the common HE-associated mutation, αL260P, in the context of a fully functional mini-spectrin. The mutation exhibited wild-type tetramer binding in univalent binding assays, but reduced binding affinity in bivalent-binding assays. Biophysical analyses demonstrated the mutation-containing domain was only modestly structurally destabilized and helical content was not significantly changed. Gel filtration analysis of the αL260P mini-spectrin indicated more compact structures for dimers and tetramers compared with wild-type. Chemical crosslinking showed structural changes in the mutant mini-spectrin dimer were primarily restricted to the vicinity of the αL260P mutation and indicated large conformational rearrangements of this region. These data indicate the mutation increased the stability of the closed dimer state, thereby reducing tetramer assembly and resulting in membrane destabilization. These results reveal a novel mechanism of erythrocyte membrane destabilization that could contribute to development of therapeutic interventions for mutations in membrane proteins containing spectrin-type domains associated with inherited disease.
MeSH term(s)	Amino Acid Sequence ; Binding Sites ; Cross-Linking Reagents/chemistry ; Elliptocytosis, Hereditary/metabolism ; Elliptocytosis, Hereditary/pathology ; Erythrocyte Membrane/chemistry ; Erythrocyte Membrane/metabolism ; Humans ; Models, Molecular ; Molecular Sequence Data ; Mutation ; Protein Binding ; Protein Multimerization ; Protein Stability ; Protein Structure, Secondary ; Protein Structure, Tertiary ; Recombinant Proteins/chemistry ; Recombinant Proteins/genetics ; Recombinant Proteins/metabolism ; Spectrin/chemistry ; Spectrin/genetics ; Spectrin/metabolism
Chemical Substances	Cross-Linking Reagents ; Recombinant Proteins ; Spectrin (12634-43-4)
Language	English
Publishing date	2013-08-23
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	80069-7
ISSN	1528-0020 ; 0006-4971
ISSN (online)	1528-0020
ISSN	0006-4971
DOI	10.1182/blood-2013-02-487702
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Article ; Online: CLIC1 and CLIC4 complement CA125 as a diagnostic biomarker panel for all subtypes of epithelial ovarian cancer.

Singha, Bipradeb / Harper, Sandra L / Goldman, Aaron R / Bitler, Benjamin G / Aird, Katherine M / Borowsky, Mark E / Cadungog, Mark G / Liu, Qin / Zhang, Rugang / Jean, Stephanie / Drapkin, Ronny / Speicher, David W

Scientific reports

2018 Volume 8, Issue 1, Page(s) 14725

Abstract: New plasma and tissue biomarkers of epithelial ovarian cancer (EOC) could improve early diagnosis and post-diagnosis clinical management. Here we investigated tissue staining and tissue secretion of CLIC1 and CLIC4 across EOC subtypes. CLIC1 and CLIC4 ... ...

Abstract	New plasma and tissue biomarkers of epithelial ovarian cancer (EOC) could improve early diagnosis and post-diagnosis clinical management. Here we investigated tissue staining and tissue secretion of CLIC1 and CLIC4 across EOC subtypes. CLIC1 and CLIC4 are two promising biomarkers we previously showed were elevated in EOC patient sera. Individually, CLIC1 or CLIC4 stained larger percentages of malignant tumors across all EOC subtypes compared with CA125, particularly early stage and mucinous tumors. CLIC4 also stained benign tumors but staining was limited to nuclei; whereas malignant tumors showed diffuse cellular staining of stromal and tumor cells. Both proteins were shed by all EOC subtypes tumors in short term organ culture at more consistent levels than CA125, supporting their potential as pan-subtype serum and tissue biomarkers. Elevated CLIC4 expression, but not CLIC1 expression, was a negative indicator of patient survival, and CLIC4 knockdown in cultured cells decreased cell proliferation and migration indicating a potential role in tumor progression. These results suggest CLIC1 and CLIC4 are promising serum and tissue biomarkers as well as potential therapeutic targets for all EOC subtypes. This justifies development of high throughput serum/plasma biomarker assays to evaluate utility of a biomarker panel consisting of CLIC1, CLIC4 and CA125.
MeSH term(s)	Aged ; Biomarkers, Tumor/blood ; Biomarkers, Tumor/genetics ; CA-125 Antigen/blood ; CA-125 Antigen/genetics ; Carcinoma, Ovarian Epithelial/blood ; Carcinoma, Ovarian Epithelial/diagnosis ; Carcinoma, Ovarian Epithelial/genetics ; Chloride Channels/blood ; Chloride Channels/genetics ; Female ; Gene Expression Regulation, Neoplastic ; Humans ; Membrane Proteins/blood ; Membrane Proteins/genetics ; Middle Aged
Chemical Substances	Biomarkers, Tumor ; CA-125 Antigen ; CLIC1 protein, human ; CLIC4 protein, human ; Chloride Channels ; MUC16 protein, human ; Membrane Proteins
Language	English
Publishing date	2018-10-03
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-018-32885-2
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