"The mitochondrial phosphatase PGAM5 is dispensable for necroptosis but promotes inflammasome activation in macrophages"

MORIWAKI, KENTA; DE ROSA, MARIA JOSE ; BERTIN, JOHN ; FARIAS LUZ, NIVEA ; ODONNELL, CAREY L. ; WELSH, RAYMOND M. ; BALAJI, SAKTHI ; GOUGH, PETER J. ; CHAN, FRANCIS KA-MING

JOURNAL OF IMMUNOLOGY

AMER ASSOC IMMUNOLOGISTS

Año: 2016 vol. 196 p. 407 - 415

0022-1767

The cytokine IL-1 β 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 a nd  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-1 β  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.