Cytoplasmic innate immune sensing by the caspase-4 non-canonical inflammasome promotes cellular senescence.

Irene Fernández-Duran,Jodie Birch,Morwenna Muir,Núria Tarrats,Vanessa Smer-Barreto,Andrea Quintanilla,Juan Carlos Acosta,Valerie G Brunton,Priya Hari,João F Passos,Fraser R Millar,Anthony B Lagnado

doi:10.1038/s41418-021-00917-6

Abstract

Cytoplasmic recognition of microbial lipopolysaccharides (LPS) in human cells is elicited by the caspase-4 and caspase-5 noncanonical inflammasomes, which induce a form of inflammatory cell death termed pyroptosis. Here we show that LPS-mediated activation of caspase-4 also induces a stress response promoting cellular senescence, which is dependent on the caspase-4 substrate gasdermin-D and the tumor suppressor p53. Furthermore, we found that the caspase-4 noncanonical inflammasome is induced and assembled in response to oncogenic RAS signaling during oncogene-induced senescence (OIS). Moreover, targeting caspase-4 expression in OIS showed its critical role in the senescence-associated secretory phenotype and the cell cycle arrest induced in cellular senescence. Finally, we observed that caspase-4 induction occurs in vivo in mouse models of tumor suppression and ageing. Altogether, we are showing that cellular senescence is induced by cytoplasmic LPS recognition by the noncanonical inflammasome and that this pathway is conserved in the cellular response to oncogenic stress.

Highlights

Cellular senescence is a cell state characterized by a proliferative cellular arrest, a secretory phenotype, macromolecular damage, and altered metabolism that can be triggered by several different stress mechanisms [1]
Here, we show that microbial pathogenic stress caused by cytoplasmic LPS accumulation and recognition by the caspase-4 noncanonical inflammasome induces a senescence response, in which sublethal levels of LPS activate the p16INK4a-pRb and p53p21CIP1 tumor suppressor pathways (Fig. S7B)
These results suggest a mechanism in which p53 controls the cellular stress responses to microbial infection downstream of caspase-4 until a certain threshold level in which gasdermin-D-dependent pyroptosis eliminates highly damaged cells, introducing a new contextdependent role for p53 in innate immune sensing [30]

Summary

INTRODUCTION

Cellular senescence is a cell state characterized by a proliferative cellular arrest, a secretory phenotype, macromolecular damage, and altered metabolism that can be triggered by several different stress mechanisms [1]. The related inflammatory caspase-4 and caspase-5 (caspase-11 in mice) function as independent PRRs for cytoplasmic microbial lipopolysaccharide (LPS) activating a noncanonical inflammasome. Activated noncanonical inflammasomes cleave the effector protein gasdermin-D, which induce a form of inflammatory programmed cell death termed pyroptosis [18,19,20]. Because the mechanism of SASP regulation by inflammasomes remains ill-defined, we decided to define the role of these inflammatory caspases in senescence. We show here that the caspase-4 noncanonical inflammasome contributes critically to the establishment of the SASP and the reinforcement of the cell cycle arrest program during OIS, in a mechanism that is independent on its catalytic activity over its downstream pyroptotic target gasdermin-D. We describe a new and critical function for cytoplasmic sensing by the caspase-4 noncanonical inflammasome in cellular senescence

RESULTS

Fernández-Duran et al 3

DISCUSSION

MATERIALS AND METHODS

Findings

ETHICAL STATEMENT