About

Dzwokai Zach Ma is an Associate Professor at UC Santa Barbara in the Life Sciences department. His research focuses on virus-host interactions, with particular emphasis on understanding the molecular mechanisms underlying these interactions. His work involves studying cellular and molecular biology aspects related to microbiology and immunology, contributing to the broader understanding of infectious diseases and host defense mechanisms.

Research topics

• Biology
• Cell biology
• Virology
• Genetics
• Environmental health
• Molecular biology
• Computational biology
• Biochemistry
• Medicine
• Chemistry

Selected publications

• Initial Characterization of WDR5B Reveals a Role in the Proliferation of Retinal Pigment Epithelial Cells

  Cells · 2024

  • Biology
  • Cell biology
  • Molecular biology

  The chromatin-associated protein WDR5 has been widely studied due to its role in histone modification and its potential as a pharmacological target for the treatment of cancer. In humans, the protein with highest sequence homology to WDR5 is encoded by the retrogene WDR5B, which remains unexplored. Here, we used CRISPR-Cas9 genome editing to generate WDR5B knockout and WDR5B-FLAG knock-in cell lines for further characterization. In contrast to WDR5, WDR5B exhibits low expression in pluripotent cells and is upregulated upon neural differentiation. Loss or shRNA depletion of WDR5B impairs cell growth and increases the fraction of non-viable cells in proliferating retinal pigment epithelial (RPE) cultures. CUT&RUN chromatin profiling in RPE and neural progenitors indicates minimal WDR5B enrichment at established WDR5 binding sites. These results suggest that WDR5 and WDR5B exhibit several divergent biological properties despite sharing a high degree of sequence homology.

  PublisherOA PDFDOI

• Host WD repeat-containing protein 5 inhibits protein kinase R-mediated integrated stress response during measles virus infection

  Journal of Virology · 2024-08-28 · 2 citations

  articleOpen accessSenior author

  Some negative-sense RNA viruses, including measles virus (MeV), share the characteristic that during their infection cycle, cytoplasmic inclusion bodies (IBs) are formed where components of the viral replication machinery are concentrated. As a foci of viral replication, how IBs act to enhance the efficiency of infection by affecting virus-host interactions remains an important topic of investigation. We previously established that upon MeV infection, the epigenetic host protein, WD repeat-containing protein 5 (WDR5), translocates to cytoplasmic viral IBs and facilitates MeV replication. We now show that WDR5 is recruited to IBs by forming a complex with IB-associated MeV phosphoprotein via a conserved binding motif located on the surface of WDR5. Furthermore, we provide evidence that WDR5 promotes viral replication by suppressing a major innate immune response pathway, the double-stranded RNA-mediated activation of protein kinase R and integrated stress response. IMPORTANCE: MeV is a pathogen that remains a global concern, with an estimated 9 million measles cases and 128,000 measles deaths in 2022 according to the World Health Organization. A large population of the world still has inadequate access to the effective vaccine against the exceptionally transmissible MeV. Measles disease is characterized by a high morbidity in children and in immunocompromised individuals. An important area of research for negative-sense RNA viruses, including MeV, is the characterization of the complex interactome between virus and host occurring at cytoplasmic IBs where viral replication occurs. Despite the progress made in understanding IB structures, little is known regarding the virus-host interactions within IBs and the role of these interactions in promoting viral replication and antagonizing host innate immunity. Herein we provide evidence suggesting a model by which MeV IBs utilize the host protein WDR5 to suppress the protein kinase R-integrated stress response pathway.

  PublisherOA PDFDOI

• Host 5′-3′ Exoribonuclease XRN1 Acts as a Proviral Factor for Measles Virus Replication by Downregulating the dsRNA-Activated Kinase PKR

  Journal of Virology · 2022 · 10 citations

  Senior authorCorresponding
  • Biology
  • Virology
  • Environmental health

  Measles virus remains a major global health threat due to its high transmissibility and significant morbidity in children and immunocompromised individuals. Although there is an effective vaccine against MeV, a large population in the world remains without access to the vaccine, contributing to more than 7,000,000 measles cases and 60,000 measles deaths in 2020 (CDC). For negative-sense RNA viruses including MeV, one active research area is the exploration of virus-host interactions occurring at cytoplasmic IBs where viral replication takes place. In this study we present evidence suggesting a model in which MeV IBs antagonize host innate immunity by recruiting XRN1 to reduce dsRNA accumulation and subsequent PKR kinase activation/ISR induction. In the absence of XRN1, the increased dsRNA level acts as a potent activator of the antiviral PKR/ISR pathway leading to suppression of global cap-dependent mRNA translation and inhibition of viral replication.

  PublisherOA PDFDOI

• Formation and Function of Liquid-Like Viral Factories in Negative-Sense Single-Stranded RNA Virus Infections

  Viruses · 2021 · 51 citations

  Senior authorCorresponding
  • Biology
  • Virology
  • Cell biology

  Liquid-liquid phase separation (LLPS) represents a major physiochemical principle to organize intracellular membrane-less structures. Studies with non-segmented negative-sense (NNS) RNA viruses have uncovered a key role of LLPS in the formation of viral inclusion bodies (IBs), sites of viral protein concentration in the cytoplasm of infected cells. These studies further reveal the structural and functional complexity of viral IB factories and provide a foundation for their future research. Herein, we review the literature leading to the discovery of LLPS-driven formation of IBs in NNS RNA virus-infected cells and the identification of viral scaffold components involved, and then outline important questions and challenges for IB assembly and disassembly. We discuss the functional implications of LLPS in the life cycle of NNS RNA viruses and host responses to infection. Finally, we speculate on the potential mechanisms underlying IB maturation, a phenomenon relevant to many human diseases.

  PublisherOA PDFDOI

• Measles Virus Forms Inclusion Bodies with Properties of Liquid Organelles

  Journal of Virology · 2019-08-05 · 195 citations

  articleOpen accessSenior author

  Measles virus remains a pathogen of significant global concern. Despite an effective vaccine, outbreaks continue to occur, and globally ∼100,000 measles-related deaths are seen annually. Understanding the molecular basis of virus-host interactions that impact the efficiency of virus replication is essential for the further development of prophylactic and therapeutic strategies. Measles virus replication occurs in the cytoplasm in association with discrete bodies, though little is known of the nature of the inclusion body structures. We recently established that the cellular protein WD repeat-containing protein 5 (WDR5) enhances MeV growth and is enriched in cytoplasmic viral inclusion bodies that include viral proteins responsible for RNA replication. Here, we show that MeV N and P proteins are sufficient to trigger the formation of WDR5-containing inclusion bodies, that these structures display properties characteristic of phase-separated liquid organelles, and that P phosphorylation together with the host dynein motor affect the efficiency of the liquid-liquid phase separation process.

  PublisherOA PDFDOI

• Role of G-proteins and phosphorylation in the distribution of AGS3 to cell puncta

  Journal of Cell Science · 2018-11-07 · 13 citations

  articleOpen access

  ABSTRACT Activator of G-protein signaling 3 (AGS3, also known as GPSM1) exhibits broad functional diversity and oscillates among different subcellular compartments in a regulated manner. AGS3 consists of a tetratricopeptide repeat (TPR) domain and a G-protein regulatory (GPR) domain. Here, we tested the hypothesis that phosphorylation of the AGS3 GPR domain regulates its subcellular distribution and functionality. In contrast to the cortical and/or diffuse non-homogeneous distribution of wild-type (WT) AGS3, an AGS3 construct lacking all 24 potential phosphorylation sites in the GPR domain localized to cytosolic puncta. This change in localization was revealed to be dependent upon phosphorylation of a single threonine amino acid (T602). The punctate distribution of AGS3-T602A was rescued by co-expression of Gαi and Gαo but not Gαs or Gαq. Following treatment with alkaline phosphatase, both AGS3-T602A and WT AGS3 exhibited a gel shift in SDS-PAGE as compared to untreated WT AGS3, consistent with a loss of protein phosphorylation. The punctate distribution of AGS3-T602A was lost in an AGS3-A602T conversion mutant, but was still present upon T602 mutation to glutamate or aspartate. These results implicate dynamic phosphorylation as a discrete mechanism to regulate the subcellular distribution of AGS3 and associated functionality.

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• Distribution of Activator of G‐Protein Signaling 3 within the Aggresomal Pathway: Role of Serine/Threonine Residues in the G‐Protein Regulatory Domain and Lysosomal Processing

  The FASEB Journal · 2017-04-01

  article

  Activator of G‐protein Signaling 3 (AGS3), a receptor independent activator of G‐protein signaling, consists of 7 tetratricopeptide repeats (TPR) and 4 G‐protein regulatory motifs (GPR) separated by a linker region. Disruption of TPR organization by point and deletion mutations stabilizes the protein in the aggresomal pathway. As an extension of this work and as part of a broader strategy to define regulatory factors affecting AGS3's subcellular “positioning”, we next examined a potential role for AGS3 phosphorylation with an initial focus on the GPR domain. AGS3 is a phosphoprotein, but sites of phosphorylation are not defined. We previously examined the subcellular location of AGS3 construct in which the 24 S/T residues in the GPR domain of the protein were mutated to alanine [phosphomutant (PM)1] and transiently expressed in COS‐7 and HEK‐293 cells. In contrast to the distribution of WT‐AGS3‐GFP to the cell cortex accompanied by a diffuse distribution in the cytosol, AGS3‐GFP‐PM1 distributed to pre‐aggresomal punctate structures in the cytoplasm and SDS‐PAGE and immunoblots of cell lysates indicated a migration shift for AGS3‐GFP‐PM1 versus AGS3‐GFP. Following cell treatment with the proteasome inhibitor MG132, AGS3‐PM1 localized to a perinuclear aggresome. To identify specific S/T residues in the GPR domain that regulate this subcellular distribution, we generated a subset of AGS3‐GFP‐PM constructs and examined their subcellular distribution following transient expression in COS‐7 and HEK‐293. Mutation of a single residue (T602A), which is located between GPR‐III and GPR‐IV was sufficient to localize AGS3 to the pre‐aggresomal punctate structures. The subcellular distribution of AGS3‐GFP‐T602A or AGS3‐GFP‐PM1 was not altered by the G[beta‐gamma] antagonist gallein (10 mM) or cell pretreatment with pertussis toxin (200ng/ml), but coexpression of G[alpha] prevented the observed distribution of the two constructs to the pre‐aggresomal punctate structures. The subcellular distribution of WT‐AGS3 was not altered by PI3K inhibitors (3‐MA (5 mM, 24 hrs), wortmannin (50 nM, 24 hrs), LY‐294,002 (10 mM, 24 hrs)) and mTOR inhibitor (rapamycin (100 nM, 24 hrs)) but inhibition of lysosome acidification by cell treatment with ammonium chloride (25 mM, 24 hrs) localized WT‐AGS3 to the pre‐aggresomal punctate structures. These data indicate that a single residue mutation in the GPR domain or in the TPR domain of AGS3 or lysosome inhibition either promote entry of AGS3 into the aggresomal pathway and/or stabilize the protein in pre‐aggresomal punctate structures. The appearance of AGS3 mutants in the pre‐aggresomal punctate structures is not observed upon interaction of the protein with its binding partner G[alpha], which together with the data generated with TPR and GPR single residue mutations, indicate that the movement of the protein into or within the aggresomal pathway may be modulated by specific signaling pathways.

  PublisherDOI

• Upon Infection, Cellular WD Repeat-Containing Protein 5 (WDR5) Localizes to Cytoplasmic Inclusion Bodies and Enhances Measles Virus Replication

  Journal of Virology · 2017-12-13 · 33 citations

  articleOpen access1st authorCorresponding

  ABSTRACT Replication of negative-strand RNA viruses occurs in association with discrete cytoplasmic foci called inclusion bodies. Whereas inclusion bodies represent a prominent subcellular structure induced by viral infection, our knowledge of the cellular protein components involved in inclusion body formation and function is limited. Using measles virus-infected HeLa cells, we found that the WD repeat-containing protein 5 (WDR5), a subunit of histone H3 lysine 4 methyltransferases, was selectively recruited to virus-induced inclusion bodies. Furthermore, WDR5 was found in complexes containing viral proteins associated with RNA replication. WDR5 was not detected with mitochondria, stress granules, or other known secretory or endocytic compartments of infected cells. WDR5 deficiency decreased both viral protein production and infectious virus yields. Interferon production was modestly increased in WDR5-deficient cells. Thus, our study identifies WDR5 as a novel viral inclusion body-associated cellular protein and suggests a role for WDR5 in promoting viral replication. IMPORTANCE Measles virus is a human pathogen that remains a global concern, with more than 100,000 measles-related deaths annually despite the availability of an effective vaccine. As measles continues to cause significant morbidity and mortality, understanding the virus-host interactions at the molecular level that affect virus replication efficiency is important for development and optimization of treatment procedures. Measles virus is an RNA virus that encodes six genes and replicates in the cytoplasm of infected cells in discrete cytoplasmic replication bodies, though little is known of the biochemical nature of these structures. Here, we show that the cellular protein WDR5 is enriched in the cytoplasmic viral replication factories and enhances virus growth. WDR5-containing protein complex includes viral proteins responsible for viral RNA replication. Thus, we have identified WDR5 as a host factor that enhances the replication of measles virus.

  PublisherOA PDFDOI

• Cellular functions of MLL/SET-family histone H3 lysine 4 methyltransferase components

  Frontiers in Biology · 2016-02-01 · 2 citations

  articleSenior author
  PublisherDOI

• WD repeat-containing protein 5 (WDR5) localizes to the midbody and regulates abscission.

  Journal of Biological Chemistry · 2015-09-01 · 2 citations

  articleOpen accessSenior author

  VOLUME 290 (2015) PAGES 8987–9001 The grant footnote should be corrected as follows. This work was supported by National Institute of Mental Health Awards 5R21MH086853-02 and 1R21MH086853-01A1 as well as by funds from the University of California Cancer Center Research Coordinating Committee and the Santa Barbara Cottage Hospital (to D. M.).

  PublisherOA PDFDOI

Recent grants

• NIH Grant R21MH08685302

  NIH · $211k · 2014

• NIH Grant R21MH08685301A1

  NIH · $177k · 2012

Frequent coauthors

• Bin Xia

  Nanchang University

  16 shared

• John E. Hearst

  12 shared

• Jeff Bailey

  University of California, Santa Barbara

  8 shared

• Lily Yeh Jan

  University of California, San Francisco

  7 shared

• Hiroshi Nikaido

  University of California, Berkeley

  7 shared

• Benjamin Groves

  University of Washington

  7 shared

• Qiang Gong

  Southwest Hospital

  7 shared

• David N. Cook

  6 shared

Labs

• Molecular, Cellular, and Developmental BiologyPI

Education

• Ph.D., Chemistry

  UC Berkeley

• M.S., Chemistry

  UC Berkeley

• B.S., Chemistry

  UC Berkeley

• Other

  UC San Francisco