Identification of a c-Jun homolog from Litopenaeus vannamei as a downstream substrate of JNK in response to WSSV infection.

c-Jun, a major substrate of c-Jun N-terminal kinase (JNK), participates in regulating gene transcription in response to various stimuli, including cytokines, stress signals, bacterial and viral infection. Results from our previous studies suggested that Litopenaeus vannamei JNK (LvJNK) could be utilized by white spot syndrome virus (WSSV) to facilitate viral replication and gene expression. In this article, a c-Jun homolog from Litopenaeus vannamei (designated as Lvc-Jun) was cloned and its role in WSSV infection was studied. Sequence analysis displayed that Lvc-Jun was a novel homolog of c-Jun family, which contained characteristic Jun and basic leucine zipper (bZIP) domains, and two conserved serine phosphorylation sites (Ser49/59). Semi-quantitative RT-PCR analysis showed that Lvc-Jun mRNAs were expressed in all examined tissues. Further investigation determined that Lvc-Jun was located in the nucleus through self-interaction and its phosphorylation levels could be reduced by JNK inhibitor, suggesting that Lvc-Jun could be regulated by LvJNK through phosphorylation and function as a transcription regulator in a homodimer. During the process of WSSV infection, the transcription levels of Lvc-Jun were up-regulated associating with the raising expression and phosphorylation levels of its protein. Moreover, TPA (12-O-tetradecanoylphorbol-13-acetate), a potent inducer of c-Jun, could remarkably promote viral immediate-early gene wsv069 transcription in crayfish hemocytes. Conclusively, our results provided experimental evidences that Lvc-Jun was engaged in WSSV infection and further implied that JNK-c-Jun signaling pathway might be important for WSSV replication and viral gene expression.

Pathogenic forms of tau inhibit kinesin-dependent axonal transport through a mechanism involving activation of axonal phosphotransferases.

Aggregated filamentous forms of hyperphosphorylated tau (a microtubule-associated protein) represent pathological hallmarks of Alzheimer's disease (AD) and other tauopathies. While axonal transport dysfunction is thought to represent a primary pathogenic factor in AD and other neurodegenerative diseases, the direct molecular link between pathogenic forms of tau and deficits in axonal transport remain unclear. Recently, we demonstrated that filamentous, but not soluble, forms of wild-type tau inhibit anterograde, kinesin-based fast axonal transport (FAT) by activating axonal protein phosphatase 1 (PP1) and glycogen synthase kinase 3 (GSK3), independent of microtubule binding. Here, we demonstrate that amino acids 2-18 of tau, comprising a phosphatase-activating domain (PAD), are necessary and sufficient for activation of this pathway in axoplasms isolated from squid giant axons. Various pathogenic forms of tau displaying increased exposure of PAD inhibited anterograde FAT in squid axoplasm. Importantly, immunohistochemical studies using a novel PAD-specific monoclonal antibody in human postmortem tissue indicated that increased PAD exposure represents an early pathogenic event in AD that closely associates in time with AT8 immunoreactivity, an early marker of pathological tau. We propose a model of pathogenesis in which disease-associated changes in tau conformation lead to increased exposure of PAD, activation of PP1-GSK3, and inhibition of FAT. Results from these studies reveal a novel role for tau in modulating axonal phosphotransferases and provide a molecular basis for a toxic gain-of-function associated with pathogenic forms of tau.