Golgi Phosphoprotein 2 Is a Novel Regulator of IL-12 Production and Macrophage Polarization

Abstract

Golgi phosphoprotein 2 (GOLPH2), a widely expressed Golgi type II transmembrane protein, has been implicated in several important physiological and pathological processes, including virus infections, cancer cell proliferation, and metastasis. However, its biological functions and mechanisms, particularly in the immune system, remain highly obscure. In this study, we report the biochemical identification of GOLPH2 from B cell lymphoma culture supernatant and show that the secreted protein could inhibit IL-12 production by dendritic cells (DCs) and IL-12-induced IFN-γ production by activated T cells. Further molecular analysis revealed that GOLPH2's IL-12-inhibiting activity was mediated through a proximal promoter element involving a previously identified transcriptional repressor named GC-binding protein that is induced during phagocytosis of apoptotic cells by macrophages. We subsequently generated global knockout mice, which exhibited little developmental abnormality but were more susceptible to LPS-induced endotoxic shock than were wild-type mice with elevated serum IL-12 levels. Furthermore, we found that GOLPH2 played a regulatory role in macrophage polarization toward the M2 type. A comprehensive analysis of gene expression profiles of activated wild-type and GOLPH2-deficient DCs by RNA sequencing uncovered mechanistic insights into the way GOLPH2 potentially modulates DC function during inflammatory insults. Our functional study of GOLPH2 helps advance the scientific understanding of the biological and pathogenic roles of this novel and intriguing molecule with great potential as a diagnostic and prognostic marker as well as a therapeutic target in many acute and chronic inflammatory disorders.

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“…Proteomic analysis using DIA-PASEF analysis of 500 ng SF by label free quantification. Functional association of significantly regulated proteins in SF were assessed by STRING analysis (Zhang et al, 2018). Similarly, proteomic serum profiling (Table 3 and Figure 4b,c) indicates a decreased activity of NETs associated proteins (Enolase (ENO1) and Calgizzarin (S100A11)) and reduced inflammation (Birkelund et al, 2020).…”

“…Several of the upregulated protein we found in SF (Table 2 and Figure 4b,c ) are implicated in the immune cell associated anti‐inflammatory processes. Golgi Membrane Protein 1 (GOLM1) has been implicated in inflammation and immunoregulation (Zhang et al, 2018 ). Genetic inactivation of GOLM1 in myeloid cells suppresses interleukin (IL)‐12 secretion and polarizes macrophage polarization (Zhang et al, 2018 ).…”

A review of GOLPH2, an oncogenic protein and novel therapeutic options for GOLPH2 driven tumours

“…But it has also been noted that GOLPH2´s function in cell physiology appears to be non-vital for development and survival. The published knockout mouse is viable and displays only a modest phenotype, namely a higher susceptibility to LPS challenge compared to wildtype littermates [6]. A truncated GOLPH2 however, seems to impair normal renal and hepatic development.…”

Tumor Microenvironment Regulation by the Endoplasmic Reticulum Stress Transmission Mediator Golgi Protein 73 in Mice

“…In addition, GP73 has immune‐dependent effects on HCC growth and metastasis. GP73 overexpression was found to attenuate antitumor T helper 1 lymphocyte response through down‐regulation of interleukin (IL)‐12A . The physiological and pathological roles of GP73 have attracted considerable attention in recent years.…”

“…GP73 overexpression was found to attenuate antitumor T helper 1 lymphocyte response through downregulation of interleukin (IL)-12A. (23) The physiological and pathological roles of GP73 have attracted considerable attention in recent years. However, the role of secreted GP73 in serum and its potential receptor remains unclear.…”