JNK regulates FoxO-dependent autophagy in neurons

Abstract

The cJun N-terminal kinase (JNK) signal transduction pathway is implicated in the regulation of neuronal function. JNK is encoded by three genes that play partially redundant roles. Here we report the creation of mice with targeted ablation of all three Jnk genes in neurons. Compound JNK-deficient neurons are dependent on autophagy for survival. This autophagic response is caused by FoxO-induced expression of Bnip3 that displaces the autophagic effector Beclin-1 from inactive Bcl-XL complexes. These data identify JNK as a potent negative regulator of FoxO-dependent autophagy in neurons.

Unspliced XBP1 controls autophagy through FoxO1

“…A recent study described a negative regulation of the transcription factor FoxO1 by XBP1s in pancreatic β cells, mediated by a physical interaction [7]. FoxO1 has key functions during aging and in the regulation of autophagy in neurons [8]. In agreement with this, an accumulation of FoxO1 was observed in the brain of XBP1-deficient mice, correlating with the enhancement of autophagy [6].…”

“…FoxO1 regulates autophagy by two distinct mechanisms: it enhances the transcription of a variety of autophagyrelated genes (i.e., atg5, lc3, beclin-1) [8]; and it is able to induce autophagy in the cytosol through its acetylation and direct binding to ATG7 [9] ( Figure 1A). In a paper recently published in Cell Research, Zhao and colleagues uncover a new role of XBP1u in the control of FoxO1 levels and autophagy [10].…”

Stress-Activated Protein Kinase MKK7 Regulates Axon Elongation in the Developing Cerebral Cortex

“…3B). Although it is possible that autophagy is a secondary effect induced by the abnormal accumulation of intermediate filaments in our mutants, it has been reported that JNK signaling is directly involved in the formation of autophagic vacuoles and autophagic cell death (Byun et al, 2009;Shimizu et al, 2010;Kim et al, 2011;Xu et al, 2011). We are currently studying our Mkk7 flox/flox Nestin-Cre mice to determine whether MKK7-JNK signaling acts to suppress autophagy in the developing brain.…”

Role of the MAPK/cJun NH 2 -terminal kinase signaling pathway in starvation-induced autophagy

“…This increased autophagy may reflect the established role of MAPK8/9 to strongly suppress the transcriptional activity of the PPARA (peroxisome proliferator activated receptor alpha) nuclear receptor [42] that can promote autophagy through increased expression of autophagic genes [43]. This role of MAPK8/9 to suppress basal autophagy in hepatocytes is similar to the established function of MAPK8, MAPK9, and MAPK10/JNK3 (mitogen-activated protein kinase 10) in neurons to suppress basal autophagy by repression of autophagic gene expression [27]. …”

“…MAPK8/9-regulated gene expression may lead to increased autophagy, but different paradigms of MAPK8/9-regulated gene expression could lead to reduced autophagy. For example, MAPK8/9-regulated gene expression suppresses basal autophagy in neurons [27]. A similar mechanism may account for MAPK8/9-mediated repression of autophagy in hepatocytes (Figure 5).…”