Involvement of Urm1, a Ubiquitin-Like Protein, in the Regulation of Oxidative Stress Response of Toxoplasma gondii

Tan, Qianqian; Wang, Jinwen; Chen, Junpeng; Liu, Xiaomei; Chen, Xiao; Xiao, Qianqian; Li, Jinxuan; Li, Hongmei; Zhao, Xiaomin; Zhang, Xiao

doi:10.1128/spectrum.02394-21

Cited by 10 publications

(15 citation statements)

References 39 publications

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“…URM1 deletion strains of T. gondii display reduced proliferation, replication, invasion, and virulence in mice. Hence, TgURM1 plays a pivotal role in T. gondii survival and Urm1 could represent a novel target for the treatment of toxoplasmosis (Tan et al , 2022 ). Our data show that the transfer of the unique thiocarboxylated C‐terminal glycine of Urm1 requires the oxidation of catalytic or peroxidatic cysteines.…”

Section: Discussionmentioning

confidence: 99%

E2/E3‐independent ubiquitin‐like protein conjugation by Urm1 is directly coupled to cysteine persulfidation

et al. 2022

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Post-translational modifications by ubiquitin-like proteins (UBLs) are essential for nearly all cellular processes. Ubiquitin-related modifier 1 (Urm1) is a unique UBL, which plays a key role in tRNA anticodon thiolation as a sulfur carrier protein (SCP) and is linked to the noncanonical E1 enzyme Uba4 (ubiquitin-like protein activator 4). While Urm1 has also been observed to conjugate to target proteins like other UBLs, the molecular mechanism of its attachment remains unknown. Here, we reconstitute the covalent attachment of thiocarboxylated Urm1 to various cellular target proteins in vitro, revealing that, unlike other known UBLs, this process is E2/E3-independent and requires oxidative stress. Furthermore, we present the crystal structures of the peroxiredoxin Ahp1 before and after the covalent attachment of Urm1. Surprisingly, we show that urmylation is accompanied by the transfer of sulfur to cysteine residues in the target proteins, also known as cysteine persulfidation. Our results illustrate the role of the Uba4-Urm1 system as a key evolutionary link between prokaryotic SCPs and the UBL modifications observed in modern eukaryotes.

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Section: Discussionmentioning

confidence: 99%

E2/E3‐independent ubiquitin‐like protein conjugation by Urm1 is directly coupled to cysteine persulfidation

et al. 2022

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“…Un-like other species, the targeting mode of TgATG12 with interacting proteins had evolved from covalent to non-covalent, retaining its original function in T. gondii [ 21 ]. Meanwhile, previous studies had shown that urmylation of TgUrm1 did not depend exclusively on the sulfide modification of TgUba1 [ 8 ]. Thus, the key role of TgUba1 in TgUrm1 urmylation remained to be explored.…”

Section: Discussionmentioning

confidence: 99%

“…Our laboratory previously identified Urm1 in T. gondii and found that deletion of Urm1 resulted in reduced tachyzoite invasion, proliferation and virulence in mice, confirming its essential importance for the survival of T. gondii . Oxidative stress was found to be a strong inducer of TgUrm1 conjugation [ 8 ]. Under oxidative stress, the interaction of TgUrm1 with the peroxiredoxin TgAhp1 exerted an anti-oxidative effect in T. gondii [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

“…Under oxidative stress, the interaction of TgUrm1 with the peroxiredoxin TgAhp1 exerted an anti-oxidative effect in T. gondii [ 9 ]. In addition, TgUrm1 seemd to be able to guide T. gondii to escape immune clearance by the host [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

“…This sulfurtransferase domain catalyzed the formation of a C-terminal thiocarboxylate on Urm1 [ 14 , 17 ]. On the basis of our previous report [ 8 ], a special gene (TGGT1_212100) with AD and RHD conserved domains was retrieved, which might be a potential activator of TgUrm1.…”

Section: Introductionmentioning

confidence: 99%

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Uba1: A Potential Ubiquitin-like Activator Protein of Urm1 in Toxoplasma gondii

Xiao

Chen

et al. 2022

IJMS

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We had shown in our previous study that TgUrm1 (ubiquitin-related Modifier 1) was involved in the regulation of anti-oxidant stress in Toxoplasma gondii by conjugating with TgAhp1. It is generally believed that Urm1 binds to target proteins through a mechanism involving Uba (ubiquitin-like activator protein). Here, we identified the TgUrm1-exclusive ubiquitin-like activator-TgUba1, which was located in the cytoplasm of Toxoplasma. TgUba1 contained three domains, including the atrophin-1 domain (ANT1), the E1-like domain (AD), and the rhodanese homology domain (RHD). We explored the interaction of TgUba1 with TgUrm1, and the AD domain was essential for the interaction of the two proteins. The TgUba1 knockout and complementary mutants were obtained based on CRISPR/Cas9 gene editing technology. The knockout of TgUba1 attenuated parasite proliferation and virulence in mice, but not invasion and egress processes, revealing the pivotal role played by TgUba1 in T. gondii survival. Meanwhile, the conjugate band of TgUrm1 was significantly reduced under oxidative stress stimulation without TgUba1, indicating that TgUba1 enhanced the targeted conjugation ability of TgUrm1 in response to oxidative stress, especially under diamide (Dia) stimulation. Furthermore, eleven TgUba1-interacting proteins were identified by proximity-based protein labeling techniques, relating them to ubiquitin-like modifications, anti-oxidative stress and metabolic regulation processes. In conclusion, TgUba1 was essential for T. gondii survival and might be a potential ubiquitin-like activator protein for TgUrm1.

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Research progress of ubiquitin and ubiquitin-like signaling in Toxoplasma gondii

Zhou,

Tian,

Liu

et al. 2024

Acta Tropica

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Involvement of Urm1, a Ubiquitin-Like Protein, in the Regulation of Oxidative Stress Response of Toxoplasma gondii

Cited by 10 publications

References 39 publications

E2/E3‐independent ubiquitin‐like protein conjugation by Urm1 is directly coupled to cysteine persulfidation

E2/E3‐independent ubiquitin‐like protein conjugation by Urm1 is directly coupled to cysteine persulfidation

Uba1: A Potential Ubiquitin-like Activator Protein of Urm1 in Toxoplasma gondii

Research progress of ubiquitin and ubiquitin-like signaling in Toxoplasma gondii

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