Pontin/Tip49 negatively regulates JNK-mediated cell death in Drosophila

Xingjun Wang,Xirui Huang,Chenxi Wu,Lei Xue

doi:10.1038/s41420-018-0074-1

Abstract

Pontin (Pont), also known as Tip49, encodes a member of the AAA+ (ATPases Associated with Diverse Cellular Activities) superfamily and plays pivotal roles in cell proliferation and growth, yet its function in cell death has remained poorly understood. Here we performed a genetic screen for dominant modifiers of Eiger-induced JNK-dependent cell death in Drosophila, and identified Pont as a negative regulator of JNK-mediated cell death. In addition, loss of function of Pont is sufficient to induce cell death and activate the transcription of JNK target gene puc. Furthermore, the epistasis analysis indicates that Pont acts downstream of Hep. Finally, we found that Pont is also required for JNK-mediated thorax development and acts as a negative regulator of JNK phosphorylation. Together, our data suggest that pont encodes a negative component of Egr/JNK signaling pathway in Drosophila through negatively regulating JNK phosphorylation, which provides a novel role of ATPase in Egr-JNK signaling.

Highlights

Pontin (Pont), known as Tip[49], Tip49a, NMP238, TAP54α, Ruvbl[1], Rvb[1], pontin[521–5], belongs to the superfamily of AAA+ ATPases (ATPases Associated with Diverse Cellular Activities), which is the extension of the known AAA family[6,7]
We showed that loss of function of Pontin promoted while gain of function of Pontin suppressed Egr-induced cell death
Consistent with our observation, dominant-negative mutant of Pontin potentiates the apoptotic activity of c-Myc and E2F152 and in HCC cells the knockdown of Pont led to spontaneous apoptosis[53]

Summary

Introduction

Pontin (Pont), known as Tip[49], Tip49a, NMP238, TAP54α, Ruvbl[1], Rvb[1], pontin[521–5], belongs to the superfamily of AAA+ ATPases (ATPases Associated with Diverse Cellular Activities), which is the extension of the known AAA family[6,7]. Pont family proteins are evolutionally conserved from yeast to humans[8], and have been reported to play vital roles in regulating gene transcription[9,10], cell proliferation[11,12] and growth[13,14,15]. The c-Jun N-terminal kinase (JNK) pathway is evolutionarily conserved from fruit flies to humans, and plays diverse biological functions including stress response, cell death, proliferation, tumor metastasis, longevity and sleep control[16,17,18,19,20,21,22,23,24,25]. We have previously performed a genetic screen for dominant modifiers of Egrinduced cell death, and have identified additional factors that regulate JNK-mediated cell death[17,38,39,40,41,42,43]

Methods

Results

Conclusion