Reciprocal regulation of Th2 and Th17 cells by PAD2-mediated citrullination

Sun, Bo; Chang, Hui-Hsin; Salinger, Ari J.; Tomita, Beverly; Bawadekar, Mandar; Holmes, Caitlyn L.; Shelef, Miriam A.; Weerapana, Eranthie; Thompson, Paul R.; Ho, I‐Cheng

doi:10.1172/jci.insight.129687

Cited by 34 publications

(45 citation statements)

References 43 publications

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“…These are PADI2 specific substrates that are not citrullinated by PADI4, which further highlights the unique features of PADI2. Interestingly, GATA3 citrullination weakens its DNA binding, whereas RORtγ citrullination strengthens its DNA binding ability, so PADI2-directed citrullination attenuates the Th2 cells differentiation and potentiates Th17 cells differentiation [9]. Taken together, these results highlight the functional implication of PADI2 in immune regulation and Th cell driven diseases.…”

Section: Padi2 Shows Specific Substrate Preferencesmentioning

confidence: 79%

“…These results highlighted that RNA-binding proteins can undergo citrullination to modulate the RNA processing. Citrullination also increases the hydrophobicity and conformation of proteins, which can potentially affect hydrogen bond formation, protein structure, protein-protein interactions and protein-nucleic acid interactions [7][8][9]. Given the significance of these interactions for essential cellular functions, citrullination may uniquely modulate cellular processes ( Figure 1).…”

Section: Introductionmentioning

confidence: 99%

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Peptidyl Arginine Deiminase 2 (PADI2)-Mediated Arginine Citrullination Modulates Transcription in Cancer

Beato

Sharma

2020

IJMS

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Protein arginine deimination leading to the non-coded amino acid citrulline remains a key question in the field of post-translational modifications ever since its discovery by Rogers and Simmonds in 1958. Citrullination is catalyzed by a family of enzymes called peptidyl arginine deiminases (PADIs). Initially, increased citrullination was associated with autoimmune diseases, including rheumatoid arthritis and multiple sclerosis, as well as other neurological disorders and multiple types of cancer. During the last decade, research efforts have focused on how citrullination contributes to disease pathogenesis by modulating epigenetic events, pluripotency, immunity and transcriptional regulation. However, our knowledge regarding the functional implications of citrullination remains quite limited, so we still do not completely understand its role in physiological and pathological conditions. Here, we review the recently discovered functions of PADI2-mediated citrullination of the C-terminal domain of RNA polymerase II in transcriptional regulation in breast cancer cells and the proposed mechanisms to reshape the transcription regulatory network that promotes cancer progression.

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Section: Padi2 Shows Specific Substrate Preferencesmentioning

confidence: 79%

Section: Introductionmentioning

confidence: 99%

Peptidyl Arginine Deiminase 2 (PADI2)-Mediated Arginine Citrullination Modulates Transcription in Cancer

Beato

Sharma

2020

IJMS

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“…Increasing evidence has highlighted the importance of PAD2 in various immune and inflammatory disorders, including rheumatoid arthritis and cancers ( 25 – 27 ). However, little is known about the functions of PAD2 in sepsis.…”

Section: Discussionmentioning

confidence: 99%

Peptidylarginine deiminase 2 has potential as both a biomarker and therapeutic target of sepsis

Tian¹,

Qu²,

Alam³

et al. 2020

JCI Insight

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Peptidylarginine deiminases (PADs) are a family of calcium-dependent enzymes that are involved in a variety of human disorders, including cancer and autoimmune diseases. Although targeting PAD4 has shown no benefit in sepsis, the role of PAD2 remains unknown. Here, we report that PAD2 is engaged in sepsis and sepsis-induced acute lung injury in both human patients and mice. Pad2 –/– or selective inhibition of PAD2 by a small molecule inhibitor increased survival and improved overall outcomes in mouse models of sepsis. Pad2 deficiency decreased neutrophil extracellular trap (NET) formation. Importantly, Pad2 deficiency inhibited Caspase-11–dependent pyroptosis in vivo and in vitro. Suppression of PAD2 expression reduced inflammation and increased macrophage bactericidal activity. In contrast to Pad2 –/– , Pad4 deficiency enhanced activation of Caspase-11–dependent pyroptosis in BM-derived macrophages and displayed no survival improvement in a mouse sepsis model. Collectively, our findings highlight the potential of PAD2 as an indicative marker and therapeutic target for sepsis.

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“…The amount of NETs has a negative impact on the barrier function of the HLMVECs ( Supplemental Figure 6 ). PAD4-KO mice lack not only the formation of NETs but also the global citrullination of other proteins that could be important for homeostasis in the lung ( 62 ). Based on the aforementioned observations, we reason that the specific pharmacologic inhibition of PAD4 activity during inflammation prevented ALI more effectively than overall PAD4 abrogation.…”

Section: Discussionmentioning

confidence: 99%

NETosis in the pathogenesis of acute lung injury following cutaneous chemical burns

Surolia¹,

Li²,

Wang³

et al. 2021

JCI Insight

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Reciprocal regulation of Th2 and Th17 cells by PAD2-mediated citrullination

Cited by 34 publications

References 43 publications

Peptidyl Arginine Deiminase 2 (PADI2)-Mediated Arginine Citrullination Modulates Transcription in Cancer

Peptidyl Arginine Deiminase 2 (PADI2)-Mediated Arginine Citrullination Modulates Transcription in Cancer

Peptidylarginine deiminase 2 has potential as both a biomarker and therapeutic target of sepsis

NETosis in the pathogenesis of acute lung injury following cutaneous chemical burns

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