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Encephalitis Is Mediated by ROP18 of Toxoplasma Gondii, a Severe Pathogen in AIDS Patients

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Encephalitis Is Mediated by ROP18 of Toxoplasma Gondii, a Severe Pathogen in AIDS Patients Encephalitis is mediated by ROP18 of Toxoplasma gondii, a severe pathogen in AIDS patients Ran Ana,b,c,1, Yuewen Tanga,b,1, Lijian Chend,1, Haijian Caia,b,1, De-Hua Laie, Kang Liua,b, Lijuan Wana,b, Linli Gonga,b, Li Yub,c, Qingli Luob,c, Jilong Shenb,c,2, Zhao-Rong Lune,2, Francisco J. Ayalaf,2, and Jian Dua,b,c,2 aDepartment of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Anhui Medical University, Hefei 230032, People’s Republic of China; bThe Key Laboratory of Pathogen Biology of Anhui Province, Anhui Medical University, Hefei 230032, People’s Republic of China; cThe Key Laboratory of Zoonoses of Anhui, Anhui Medical University, Hefei 230032, People’s Republic of China; dDepartment of Anesthesiology, The First Affiliated Hospital of Anhui Medical University, Hefei 230032, People’s Republic of China; eCenter for Parasitic Organisms, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou 510275, People’s Republic of China; and fDepartment of Ecology and Evolutionary Biology, Ayala School of Biological Sciences, University of California, Irvine, CA 92697 Contributed by Francisco J. Ayala, April 19, 2018 (sent for review January 22, 2018; reviewed by Chunlei Su and Masahiro Yamamoto) The neurotropic parasite Toxoplasma gondii is a globally distrib- Rhoptry protein 18 (ROP18), a serine (Ser)/threonine (Thr) ki- uted parasitic protozoan among mammalian hosts, including hu- nase secreted by Toxoplasma rhoptries into the parasitophorous mans. During the course of infection, the CNS is the most commonly vacuole (PV) and host cytosol, was identified as a major virulence damaged organ among invaded tissues. The polymorphic rhoptry factor (12, 13). Previous studies have demonstrated that ROP18 can protein 18 (ROP18) is a key serine (Ser)/threonine (Thr) kinase that phosphorylate several targets in the host cell, including immunity- phosphorylates host proteins to modulate acute virulence. However, related GTPases (IRGs) (14, 15) and ATF6β (16), to mediate the basis of neurotropism and the specific substrates through which virulence during infection. Our studies revealed that ROP18 ROP18 exerts neuropathogenesis remain unknown. Using mass spec- phosphorylates the host NF-κB p65 and targets this protein to trometry, we performed proteomic analysis of proteins that selec- ubiquitin-dependent degradation, thus inhibiting the NF-κB tively bind to active ROP18 and identified RTN1-C, an endoplasmic pathway in infected macrophages (17). In addition, our recent reticulum (ER) protein that is preferentially expressed in the CNS. studies have demonstrated that ROP18 can stimulate neural cell We demonstrated that ROP18 is associated with the N-terminal por- death by inducing the ER stress-mediated apoptosis pathway (10). tion of RTN1-C and specifically phosphorylates RTN1-C at Ser7/ However, host proteins, especially those preferentially expressed in MEDICAL SCIENCES 134 and Thr4/8/118. ROP18 phosphorylation of RTN1-C triggers ER nervous tissues, targeted by ROP18 and its associated molecular stress-mediated apoptosis in neural cells. Remarkably, ROP18 phos- mechanism remain unclear. phorylation of RTN1-C enhances glucose-regulated protein 78 (GRP78) Herein, we report that an ER-associated protein called retic- acetylation by attenuating the activity of histone deacetylase (HDAC), ulon 1-C (RTN1-C) is a substrate that can be phosphorylated by and this event is associated with an increase of neural apoptosis. These ROP18. ROP18 phosphorylates RTN1-C and triggers ER stress- results clearly demonstrate that both RTN1-C and HDACs are involved mediated apoptosis in neural cells. Moreover, phosphorylated in T. gondii ROP18-mediated pathogenesis of encephalitis during RTN1-C enhances GRP78 acetylation by attenuating the activity Toxoplasma infection. of histone deacetylase (HDAC), and this event is associated with ROP18 | RTN1-C | phosphorylation | ER stress | neural apoptosis Significance he obligate intracellular protozoan, Toxoplasma gondii, in- As a neurotropic parasite, Toxoplasma predominantly interacts fects a broad range of hosts, including humans. As a neuro- T with neurons throughout CNS infection and causes severe tropic parasite, it exhibits a strong predilection for interacting damage to the brain. In patients with severe immune dys- with neurons throughout the CNS (1–3). Toxoplasmic encepha- function, dormant encysted bradyzoites can reactivate into litis (TE) is the most serious outcome of toxoplasmosis due to fast-replicating tachyzoites and may cause damage to the reactivation of cysts in the brain. In AIDS, cancer, or patients with brain. We report that an endoplasmic reticulum (ER)-associated severe immune dysfunction, dormant encysted bradyzoites can protein, RTN1-C, is a substrate of ROP18 kinase. ROP18 phos- reactivate into fast-replicating tachyzoites and cause severe dam- phorylation of RTN1-C triggers ER stress-mediated apoptosis. age to the brain (4). Identifying essential host factors, particularly Phosphorylated RTN1-C enhances GRP78 acetylation via attenu- those expressed in the nervous system, will represent a major step ating the activity of histone deacetylases and is associated with forward to further understanding of pathogenesis of TE. neural apoptosis. These results link Toxoplasma’s effector ROP18 Endoplasmic reticulum (ER) stress is triggered by a loss of to RTN1-C, the CNS predominantly expressed protein, as well as ER homeostasis in the ER, resulting in the accumulation of misfolded stress-induced apoptosis via GRP78 acetylation, which may pro- proteins in the ER lumen (5). Numerous disturbances, including a vide new insight into the preferential invasion of the central diverse spectrum of toxins or noxious stimuli, cause accumulation of nervous system by Toxoplasma. unfolded proteins in the ER, triggering a well-characterized reaction “ ” to ER stress termed the unfolded protein response (UPR). One Author contributions: R.A., Y.T., L.C., H.C., J.S., Z.-R.L., and J.D. designed research; R.A., of them, the glucose-regulated protein 78 (GRP78) plays a central Y.T., L.C., H.C., D.-H.L., K.L., L.W., L.G., L.Y., and Q.L. performed research; R.A., D.-H.L., J.S., role in activating the UPR. When the ER is “stressed” by unfolded Z.-R.L., F.J.A., and J.D. analyzed data; and J.S., Z.-R.L., F.J.A., and J.D. wrote the paper. proteins, GRP78 binds to the unfolded proteins in the ER, freeing Reviewers: C.S., University of Tennessee; and M.Y., Osaka University. its client proteins to trigger the UPR. However, under prolonged The authors declare no conflict of interest. ER stress, the UPR can also induce apoptotic cell death through Published under the PNAS license. activation of caspase-12, CHOP, and/or c-JUN NH2-terminal ki- 1R.A., Y.T., L.C., and H.C. contributed equally to this work. nase (JNK) (5). Increasing evidence indicates that intracellular 2To whom correspondence may be addressed. Email: [email protected], lsslzr@mail. pathogens and viruses alike often disturb ER homeostasis and lead sysu.edu.cn, [email protected], or [email protected]. to the ER stress response during infection (6, 7). As an obligate This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. intracellular protozoan, T. gondii has been shown previously to 1073/pnas.1801118115/-/DCSupplemental. cause ER stress and induce apoptotic cell death (2, 8–11). www.pnas.org/cgi/doi/10.1073/pnas.1801118115 PNAS Latest Articles | 1of9 Downloaded by guest on October 1, 2021 neural apoptosis. The finding offers clues to gain a better un- cerebral cortex of mice infected with the ROP18-WT RH or wild- derstanding of the neuropathology of TE. type RH tachyzoites compared with the uninfected group. Re- markably, the active caspase-3 staining of the mice infected with the Results ROP 18-WT RH was significantly increased compared with the ROP18 Kinase Activity Is Required for Neural Apoptosis. To test the ROP18-KD RH– or Δrop18 RH-infected group. The specificity of hypothesis that Toxoplasma–CNS host cell interactions occur the staining was confirmed by negative control with IgG and base- during acute toxoplasmosis, initial studies were carried out to line weak staining in the normal brain (SI Appendix,Fig.S1A and detect encephalitis in brain tissues. As expected, necrosis and B). Neuronal damage was then examined using immunofluorescent inflammation were present around Toxoplasma cysts (Fig. 1A). staining of NeuN (a specific neuron marker) and active caspase-3 More importantly, analyses of immunofluorescent staining of staining. Consistently, the results demonstrated that the ROP18-WT ROP18 and active caspase-3 showed that a high degree of neural RH strain induced significant levels of active caspase-3 cleavage– apoptosis was present in the cortex of immunosuppressed mice positive neuronal cells, whereas infection with the ROP18-KD strain compared with the control, suggesting the ROP18-mediated or Δrop18 RH failed to induce active caspase-3 (Fig. 1C). To in- neural apoptosis in TE (Fig. 1B). To explore whether ROP18 vestigate whether ROP18 kinase activity is required for neural ap- kinase activity plays a pivotal role in the death of neurons during optosis, we infected Neuro2a cells with ROP18-WT, ROP18-KD, or infection, each individual in the group of BALB/c mice was in- Δrop18 RH tachyzoites and performed flow cytometry analysis. fected i.p. with 1 × 103 tachyzoites from parasites overexpressing ROP18-WT RH tachyzoites, compared with ROP18-KD or Δrop18 wild-type ROP18 reticulon homology (ROP18-WT RH), parasites RH tachyzoites, significantly enhanced neural apoptosis (SI Ap- overexpressing kinase-deficient ROP18 (S394A) RH (ROP18-KD pendix,Fig.S1C and D). Collectively, these results suggest that RH), ROP18 knockout Δku80 RH strain (Δrop18 RH), or wild-type ROP18 kinase activity is required for neural apoptosis. RH tachyzoites. Pathology in the brain tissues of animals was ex- amined as soon as obvious clinical manifestations were observed. To Identification of RTN1-C as a ROP18-Interacting Host Protein.
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