TP53INP1, a tumor suppressor, interacts with LC3 and ATG8-family proteins through the LC3-interacting region (LIR) and promotes autophagic cell death

M. SEILLIER, S. PEUGET, O. GAYET, C.GAUTHIER, P.N'GUESSAN, M. MONTE, A.CARRIER, J.L.IOVANNA, N.DUSETTI

CELL DEATH AND DIFFERENTIATION

NATURE PUBLISHING GROUP

Lugar: Londres; Año: 2012 vol. 19 p. 1525 - 1535

1350-9047

TP53INP1 (tumor protein 53-induced nuclear protein 1) is a tumor suppressor, whose expression is downregulated in cancersfrom different organs. It was described as a p53 target gene involved in cell death, cell-cycle arrest and cellular migration. In thiswork, we show that TP53INP1 is also able to interact with ATG8-family proteins and to induce autophagy-dependent cell death.In agreement with this finding, we observe that TP53INP1, which is mainly nuclear, relocalizes in autophagosomes duringautophagy where it is eventually degraded. TP53INP1-LC3 interaction occurs via a functional LC3-interacting region (LIR).Inactivating mutations of this sequence abolish TP53INP1-LC3 interaction, relocalize TP53INP1 in autophagosomes anddecrease TP53INP1 ability to trigger cell death. Interestingly, TP53INP1 binds to ATG8-family proteins with higher affinity thanp62, suggesting that it could partially displace p62 from autophagosomes, modifying thereby their composition. Moreover,silencing the expression of autophagy related genes (ATG5 or Beclin-1) or inhibiting caspase activity significantly decreases celldeath induced by TP53INP1. These data indicate that cell death observed after TP53INP1-LC3 interaction depends on bothautophagy and caspase activity.We conclude that TP53INP1 could act as a tumor suppressor by inducing cell death by caspasedependentautophagy.