The Mitochondrial Phosphatase PGAM5 Is Dispensable for Necroptosis but Promotes Inflammasome Activation in Macrophages

Abstract

The cytokine IL-1β is intimately linked to many pathological inflammatory conditions. Mature IL-1β secretion requires cleavage by the inflammasome. Recent evidence indicates that many cell death signal adaptors have regulatory roles in inflammasome activity. These include the apoptosis inducers FADD and caspase 8, and the necroptosis kinases receptor interacting protein kinase 1 (RIPK1) and RIPK3. Phosphoglycerate mutase family member 5 (PGAM5) is a mitochondrial phosphatase that has been reported to function downstream of RIPK3 to promote necroptosis and IL-1β secretion. To interrogate the biological function of PGAM5, we generated Pgam5−/− mice. We found that Pgam5−/− mice were smaller in size compared with wild type littermates, and male Pgam5−/− mice were born at sub-Mendelian ratio. Despite these growth and survival defects, Pgam5−/− cells responded normally to multiple inducers of apoptosis and necroptosis. Rather, we found that PGAM5 is critical for IL-1β secretion in response to NLRP3 and AIM2 inflammasome agonists. Moreover, vesicular stomatosis virus (VSV)-induced IL-1β secretion was impaired in Pgam5−/− bone marrow derived macrophages (BMDMs), but not in Ripk3−/− BMDMs, indicating that PGAM5 functions independent of RIPK3 to promote inflammasome activation. Mechanistically, PGAM5 promotes ASC polymerization, maintenance of mitochondrial integrity, and optimal ROS production in response to inflammasome signals. Hence, PGAM5 is a novel regulator of inflammasome and caspase 1 activity that functions independently of RIPK3.

The phosphatase Pgam5 antagonizes Wnt/β-Catenin signaling in embryonic anterior-posterior axis patterning

“…Unlike our observations in Xenopus development, no significant developmental phenotype has been reported for Pgam5 knockout mice, except for a general reduction in size and body mass, and increased postnatal lethality (Lu et al, 2014;Moriwaki et al, 2016). Interestingly, we also observed increased lethality when higher doses of Pgam5 MO were injected, which might correspond to the observations in Pgam5 knockout mice.…”

“…However, these phenotypes would also be explained by a loss of anterior cells (Offner et al, 2005). Necroptosis-promoting and -protective roles, as well as pro-and anti-apoptotic functions of Pgam5 have been described (Ishida et al, 2012;Lenhausen et al, 2016;Lu et al, 2016;Moriwaki et al, 2016;Zhou et al, 2012). However, we have not detected any local or global changes in cell death or apoptosis in Pgam5 morphant Xenopus embryos, indicating that regulation of cell death does not represent the major early developmental function of Pgam5 in Xenopus.…”

“…3B). Pgam5 has been functionally implicated in apoptosis, necroptosis and mitophagy, although it apparently acts as positive or negative regulator, depending on the experimental context (Chen et al, 2014;Ishida et al, 2012;Lenhausen et al, 2016;Lu et al, 2016;Moriwaki et al, 2016;Wang et al, 2012). Increased cell death in the anterior ectoderm might lead to a loss of head structures, while inhibition of cell death in early Xenopus embryos results in an expansion of neuroectoderm (Offner et al, 2005;Yeo and Gautier, 2003).…”

Mitochondrial-Related Gene Expression and Macrophage Signatures in Non-Small Cell Lung Cancer, Including Patients with Emphysema as Co-Morbidity

“…Increased mitochondrial turnover may also lead to a change in the metabolic phenotype of the alveolar macrophages which is known to be related to their immunomodulatory phenotypes [43]. The activation of PGAM5 in the alveolar macrophages may also lead to the activation of the inflammasome, which is known to be important in triggering the inflammatory reaction in COPD [38]. Overall, our data suggests that factors released from specific subtypes of lung macrophages may affect cancer progression and survival.…”

“…PGAM5 catalyses the dephosphorylation of FUNDC1 which enhances its interaction with microtubule-associated protein 1A/1B-light chain 3, leading to mitophagy [37]. PGAM5 also promotes inflammasome activation in macrophages [38].…”