Pyroptosis leads to loss of centrosomal integrity in macrophages

Siyi Bai, Fatima Martin-Sanchez, David Brough, Gloria Lopez-Castejon

Research output: Contribution to journalArticlepeer-review

Abstract

NLRP3 forms a multiprotein inflammasome complex to initiate the inflammatory response
when macrophages sense infection or tissue damage, which leads to caspase-1 activation,
maturation and release of the inflammatory cytokines interleukin-1β (IL-1β) and IL-18 and
Gasdermin-D (GSDMD) mediated pyroptosis. NLRP3 inflammasome activity must be
controlled as unregulated and chronic inflammation underlies inflammatory and autoimmune diseases. Several findings uncovered that NLRP3 inflammasome activity is under the regulation of centrosome localized proteins such as NEK7 and HDAC6, however, whether the centrosome composition or structure is altered during the inflammasome activation is not
known. Our data show that levels of the centrosomal scaffold protein pericentrin (PCNT) are
reduced upon NLRP3 inflammasome activation via different activators in human and murine macrophages. PCNT loss occurs in the presence of membrane stabilizer punicalagin,
suggesting this is not a consequence of membrane rupture. We found that PCNT loss is
dependent on NLRP3 and active caspases as MCC950 and pan caspase inhibitor ZVAD
prevent its degradation. Moreover, caspase-1 and GSDMD are both required for this NLRP3-
mediated PCNT loss because absence of caspase-1 or GSDMD triggers an alternative
regulation of PCNT via its cleavage by caspase-3 in response to nigericin stimulation. PCNT
degradation occurs in response to nigericin, but also other NLRP3 activators including
lysomotropic agent L-Leucyl-L-Leucine methyl ester (LLOMe) and hypotonicity but not AIM2 activation. Our work reveals that the NLRP3 inflammasome activation alters centrosome composition highlighting the need to further understand the role of this organelle during
inflammatory responses.
Original languageEnglish
JournalCell death discovery
Publication statusAccepted/In press - 27 Jun 2024

Keywords

  • Centrosome
  • NLRP3 Inflammasome
  • Pyroptosis
  • Caspases

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