Pei Zhou

Overview:

Protein-protein interactions play a pivotal role in the regulation of various cellular processes. The formation of higher order protein complexes is frequently accompanied by extensive structural remodeling of the individual components, varying from domain re-orientation to induced folding of unstructured elements. Nuclear Magnetic Resonance (NMR) spectroscopy is a powerful tool for macromolecular structure determination in solution. It has the unique advantage of being capable of elucidating the dynamic behavior of proteins during the process of recognition. Recent advances in NMR techniques have enabled the study of significantly larger proteins and protein complexes. These innovations have also led to faster and more accurate structure determination. My research interests focus on the exploration of molecular recognition and conformation variability of protein complexes in crucial biomedical processes using state-of-the-art NMR techniques.

Positions:

Professor of Biochemistry

Biochemistry
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

Ph.D. 1998

Harvard University

Post-Doct Fellow, Biological Chemistry

Harvard University

Grants:

Structural Biology and Biophysics Training Program

Administered By
Basic Science Departments
Awarded By
National Institutes of Health
Role
Mentor
Start Date
End Date

Biochemical and functional investigation of the novel enzymatic activities of MESH1

Administered By
Molecular Genetics and Microbiology
Awarded By
National Institutes of Health
Role
Co-Principal Investigator
Start Date
End Date

Regulation of Germline Stem Cell Division in Drosophila

Awarded By
National Institutes of Health
Role
Consultant
Start Date
End Date

High sensitivity multi-purpose electron paramagnetic resonance spectroscopy for biotechnological and biomedical research

Administered By
Biochemistry
Awarded By
North Carolina Biotechnology Center
Role
Collaborating Investigator
Start Date
End Date

Discovery and validation of broadly effective LpxH inhibitors as novel therapeutics against multi-drug resistant Gram-negative pathogens

Administered By
Biochemistry
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Publications:

The regulation of ferroptosis by MESH1 through the activation of the integrative stress response.

All organisms exposed to metabolic and environmental stresses have developed various stress adaptive strategies to maintain homeostasis. The main bacterial stress survival mechanism is the stringent response triggered by the accumulation "alarmone" (p)ppGpp, whose level is regulated by RelA and SpoT. While metazoan genomes encode MESH1 (Metazoan SpoT Homolog 1) with ppGpp hydrolase activity, neither ppGpp nor the stringent response is found in metazoa. The deletion of Mesh1 in Drosophila triggers a transcriptional response reminiscent of the bacterial stringent response. However, the function of MESH1 remains unknown until our recent discovery of MESH1 as the first cytosolic NADPH phosphatase that regulates ferroptosis. To further understand whether MESH1 knockdown triggers a similar transcriptional response in mammalian cells, here, we employed RNA-Seq to analyze the transcriptome response to MESH1 knockdown in human cancer cells. We find that MESH1 knockdown induced different genes involving endoplasmic reticulum (ER) stress, especially ATF3, one of the ATF4-regulated genes in the integrative stress responses (ISR). Furthermore, MESH1 knockdown increased ATF4 protein, eIF2a phosphorylation, and induction of ATF3, XBPs, and CHOP mRNA. ATF4 induction contributes to ~30% of the transcriptome induced by MESH1 knockdown. Concurrent ATF4 knockdown re-sensitizes MESH1-depleted RCC4 cells to ferroptosis, suggesting its role in the ferroptosis protection mediated by MESH1 knockdown. ATF3 induction is abolished by the concurrent knockdown of NADK, implicating a role of NADPH accumulation in the integrative stress response. Collectively, these results suggest that MESH1 depletion triggers ER stress and ISR as a part of its overall transcriptome changes to enable stress survival of cancer cells. Therefore, the phenotypic similarity of stress tolerance caused by MESH1 removal and NADPH accumulation is in part achieved by ISR to regulate ferroptosis.
Authors
Lin, C-C; Ding, C-KC; Sun, T; Wu, J; Chen, K-Y; Zhou, P; Chi, J-T
MLA Citation
Lin, Chao-Chieh, et al. “The regulation of ferroptosis by MESH1 through the activation of the integrative stress response.Cell Death Dis, vol. 12, no. 8, July 2021, p. 727. Pubmed, doi:10.1038/s41419-021-04018-7.
URI
https://scholars.duke.edu/individual/pub1488796
PMID
34294679
Source
pubmed
Published In
Cell Death & Disease
Volume
12
Published Date
Start Page
727
DOI
10.1038/s41419-021-04018-7

Francisella FlmX broadly affects lipopolysaccharide modification and virulence.

The outer membrane protects Gram-negative bacteria from the host environment. Lipopolysaccharide (LPS), a major outer membrane constituent, has distinct components (lipid A, core, O-antigen) generated by specialized pathways. In this study, we describe the surprising convergence of these pathways through FlmX, an uncharacterized protein in the intracellular pathogen Francisella. FlmX is in the flippase family, which includes proteins that traffic lipid-linked envelope components across membranes. flmX deficiency causes defects in lipid A modification, core remodeling, and O-antigen addition. We find that an F. tularensis mutant lacking flmX is >1,000,000-fold attenuated. Furthermore, FlmX is required to resist the innate antimicrobial LL-37 and the antibiotic polymyxin. Given FlmX's central role in LPS modification and its conservation in intracellular pathogens Brucella, Coxiella, and Legionella, FlmX may represent a novel drug target whose inhibition could cripple bacterial virulence and sensitize bacteria to innate antimicrobials and antibiotics.
Authors
Chin, C-Y; Zhao, J; Llewellyn, AC; Golovliov, I; Sjöstedt, A; Zhou, P; Weiss, DS
MLA Citation
Chin, Chui-Yoke, et al. “Francisella FlmX broadly affects lipopolysaccharide modification and virulence.Cell Rep, vol. 35, no. 11, June 2021, p. 109247. Pubmed, doi:10.1016/j.celrep.2021.109247.
URI
https://scholars.duke.edu/individual/pub1485959
PMID
34133919
Source
pubmed
Published In
Cell Reports
Volume
35
Published Date
Start Page
109247
DOI
10.1016/j.celrep.2021.109247

REV1 Inhibition Enhances Radioresistance and Autophagy

<jats:p>Cancer therapy resistance is a persistent clinical challenge. Recently, inhibition of the mutagenic translesion synthesis (TLS) protein REV1 was shown to enhance tumor cell response to chemotherapy by triggering senescence hallmarks. These observations suggest REV1&amp;rsquo;s important role in determining cancer cell response to chemotherapy. Whether REV1 inhibition would similarly sensitize cancer cells to radiation treatment is unknown. This study reports a lack of radiosensitization in response to REV1 inhibition by small molecule inhibitors in ionizing radiation-exposed cancer cells. Instead, REV1 inhibition unexpectedly triggers autophagy, which is a known biomarker of radioresistance. Collectively, we report a possible role of REV1 TLS protein in determining cancer treatment outcomes depending upon the type of DNA damage inflicted. Furthermore, we discover REV1 inhibition directly triggers autophagy, an uncharacterized REV1 phenotype, with significant bearing on cancer treatment regimens.</jats:p>
Authors
Ikeh, K; Lamkin, E; Crompton, A; Deutsch, J; Fisher, K; Gray, ME; Argyle, D; Lim, W; Korzhnev, D; Hadden, MK; Hong, J; Zhou, P; Chatterjee, N
MLA Citation
Ikeh, Kanayo, et al. REV1 Inhibition Enhances Radioresistance and Autophagy. MDPI AG. Crossref, doi:10.20944/preprints202109.0202.v1.
URI
https://scholars.duke.edu/individual/pub1497077
Source
crossref
DOI
10.20944/preprints202109.0202.v1

Adaptive responses of Pseudomonas aeruginosa to treatment with antibiotics.

Pseudomonas aeruginosa is among the highest priority pathogens for drug development, because of its resistance to antibiotics, extraordinary adaptability, and persistence. Anti-pseudomonal research is strongly encouraged to address the acute scarcity of innovative antimicrobial lead structures. In an effort to understand the physiological response of P. aeruginosa to clinically relevant antibiotics, we investigated the proteome after exposure to ciprofloxacin, levofloxacin, rifampicin, gentamicin, tobramycin, azithromycin, tigecycline, polymyxin B, colistin, ceftazidime, meropenem, and piperacillin/tazobactam. We further investigated the response to CHIR-90, which represents a promising class of lipopolysaccharide biosynthesis inhibitors currently under evaluation. Radioactive pulse-labeling of newly synthesized proteins followed by 2D-PAGE was used to monitor the acute response of P. aeruginosa to antibiotic treatment. The proteomic profiles provide insights into the cellular defense strategies for each antibiotic. A mathematical comparison of these response profiles based on upregulated marker proteins revealed similarities of responses to antibiotics acting on the same target area. This study provides insights into the effects of commonly used antibiotics on P. aeruginosa and lays the foundation for the comparative analysis of the impact of novel compounds with precedented and unprecedented modes of action.
Authors
Wüllner, D; Gesper, M; Haupt, A; Liang, X; Zhou, P; Dietze, P; Narberhaus, F; Bandow, JE
MLA Citation
Wüllner, Dominik, et al. “Adaptive responses of Pseudomonas aeruginosa to treatment with antibiotics.Antimicrob Agents Chemother, Nov. 2021, p. AAC0087821. Pubmed, doi:10.1128/AAC.00878-21.
URI
https://scholars.duke.edu/individual/pub1500574
PMID
34748386
Source
pubmed
Published In
Antimicrob Agents Chemother
Published Date
Start Page
AAC0087821
DOI
10.1128/AAC.00878-21

Rev1 inhibition enhances radioresistance and autophagy

Cancer therapy resistance is a persistent clinical challenge. Recently, inhibition of the mutagenic translesion synthesis (TLS) protein REV1 was shown to enhance tumor cell response to chemotherapy by triggering senescence hallmarks. These observations suggest REV1’s important role in determining cancer cell response to chemotherapy. Whether REV1 inhibition would similarly sensitize cancer cells to radiation treatment is unknown. This study reports a lack of radiosensitization in response to REV1 inhibition by small molecule inhibitors in ionizing radiation-exposed cancer cells. Instead, REV1 inhibition unexpectedly triggers autophagy, which is a known biomarker of radioresistance. We report a possible role of the REV1 TLS protein in determining cancer treatment outcomes depending upon the type of DNA damage inflicted. Furthermore, we discover that REV1 inhibition directly triggers autophagy, an uncharacterized REV1 phenotype, with a significant bearing on cancer treatment regimens.
Authors
Ikeh, KE; Lamkin, EN; Crompton, A; Deutsch, J; Fisher, KJ; Gray, M; Argyle, DJ; Lim, WY; Korzhnev, DM; Kyle Hadden, M; Hong, J; Zhou, P; Chatterjee, N
MLA Citation
Ikeh, K. E., et al. “Rev1 inhibition enhances radioresistance and autophagy.” Cancers, vol. 13, no. 21, Nov. 2021. Scopus, doi:10.3390/cancers13215290.
URI
https://scholars.duke.edu/individual/pub1499235
Source
scopus
Published In
Cancers
Volume
13
Published Date
DOI
10.3390/cancers13215290