PDLIM2 Inhibits T Helper 17 Cell Development and Granulomatous Inflammation Through Degradation of STAT3

Abstract

Granuloma formation is an important host defense mechanism against intracellular bacteria; however, uncontrolled granulomatous inflammation is pathologic. T helper 17 (TH17) cells are thought to have a pathogenic role in autoimmune and inflammatory diseases, including in granulomas. Here, we report that the PDZ-LIM domain protein PDLIM2 inhibited TH17 cell development and granulomatous responses by acting as a nuclear ubiquitin E3 ligase that targeted signal transducer and activator of transcription 3 (STAT3), a transcription factor critical for the commitment of naïve CD4+ T cells to the TH17 lineage. PDLIM2 promoted the polyubiquitination and proteasomal degradation of STAT3, thereby disrupting STAT3-mediated gene activation. Deficiency in PDLIM2 resulted in the accumulation of STAT3 in the nucleus, enhanced the extent of TH17 cell differentiation, and exacerbated granuloma formation. This study delineates an essential role for PDLIM2 in inhibiting TH17 cell-mediated inflammatory responses by suppressing STAT3 signaling and provides a potential therapeutic target for the treatment of autoimmune diseases.

Oncovirus Kaposi Sarcoma Herpesvirus (KSHV) Represses Tumor Suppressor PDLIM2 to Persistently Activate Nuclear Factor κB (NF-κB) and STAT3 Transcription Factors for Tumorigenesis and Tumor Maintenance

“…Under normal conditions, activation of NF-B and STAT3 is usually transient. One essential mechanism for terminating activation of both NF-B RelA and STAT3 involves polyubiquitination and proteasomal degradation of their nuclear activated forms mediated by PDLIM2 (33)(34)(35). Accordingly, the expression of PDLIM2 has been found to be epigenetically repressed in several tumors associated with persistent activation of RelA (36 -39).…”

A New STAT3-binding Partner, ARL3, Enhances the Phosphorylation and Nuclear Accumulation of STAT3

“…In addition, the expression and activity of STAT3 are regulated at both pre-and post-transcription, and STAT3 functions are also dependent on its intracellular localization (12). We have identified several STAT3-interacting molecules, such as death domain-associated protein (DAXX) (13), zipper-interacting protein kinase (ZIPK) (14), Krüppel-associated box-associated protein 1 (KAP1) (15), PDZ and LIM domain 2 (PDLIM2) (16), Y14 (17,18), and signal-transducing adaptor protein-2 (STAP-2) (19,20). DAXX negatively and ZIPK positively regulate STAT3-mediated transactivation (13,14).…”

“…Within the nucleus, KAP1 regulates the phosphorylation and transactivation of STAT3 by interacting with HDAC3 (15). PDLIM2, a nuclear E3 ligase for STAT3, terminates STAT3-mediated signaling (16). Y14 influences tyrosine phosphorylation and positively regulates cytokine-induced STAT3 transactivation (17,18).…”

The E3 Deubiquitinase USP17 Is a Positive Regulator of Retinoic Acid-related Orphan Nuclear Receptor γt (RORγt) in Th17 Cells

“…PDZ-LIM domain protein (PDLIM2), a nuclear ubiquitin E3 ligase, inhibits TH17 cell-mediated inflammatory responses by suppressing STAT3 signaling (14). The ubiquitin-specific protease USP25 has been identified as a negative regulator of IL-17-mediated signaling and inflammation through the removal of ubiquitination on TRAF5 and TRAF6 (15), and USP18 has been found to regulate T cell activation and Th17 cell differentiation by deubiquitinating the TAK1-TAB1 complex (16).…”