scholarly journals Amyloid-β(1−42) Fibrillar Precursors Are Optimal for Inducing Tumor Necrosis Factor-α Production in the THP-1 Human Monocytic Cell Line

Biochemistry ◽  
2009 ◽  
Vol 48 (38) ◽  
pp. 9011-9021 ◽  
Author(s):  
Deepa Ajit ◽  
Maria L. D. Udan ◽  
Geeta Paranjape ◽  
Michael R. Nichols
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Amyloid Β ◽  
Monocytic Cell ◽  
Monocytic Cell Line ◽  
Human Monocytic Cell Line ◽  
Human Monocytic Cell ◽  
Factor Α ◽  
Necrosis Factor

scholarly journals Tumor Necrosis Factor-α–elicited Stimulation of γ-Secretase Is Mediated by c-Jun N-terminal Kinase-dependent Phosphorylation of Presenilin and Nicastrin

2008 ◽  
Vol 19 (10) ◽  
pp. 4201-4212 ◽  
Author(s):  
Lan-Hsin Kuo ◽  
Ming-Kuan Hu ◽  
Wen-Ming Hsu ◽  
Ying-Tsen Tung ◽  
Bo-Jeng Wang ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Phosphorylation Site ◽  
Amyloid Β ◽  
Site Directed Mutagenesis ◽  
Secretase Activity ◽  
Tnf Α ◽  
Factor Α ◽  
Necrosis Factor

γ-Secretase is a multiprotein complex composed of presenilin (PS), nicastrin (NCT), Aph-1, and Pen-2, and it catalyzes the final proteolytic step in the processing of amyloid precursor protein to generate amyloid-β. Our previous results showed that tumor necrosis factor-α (TNF-α) can potently stimulate γ-secretase activity through a c-Jun N-terminal kinase (JNK)-dependent pathway. Here, we demonstrate that TNF-α triggers JNK-dependent serine/threonine phosphorylation of PS1 and NCT to stimulate γ-secretase activity. Blocking of JNK activity with a potent JNK inhibitor (SP600125) reduces TNF-α–triggered phosphorylation of PS1 and NCT. Consistent with this, we show that activated JNKs can be copurified with γ-secretase complexes and that active recombinant JNK2 can promote the phosphorylation of PS1 and NCT in vitro. Using site-directed mutagenesis and a synthetic peptide, we clearly show that the Ser319Thr320 motif in PS1 is an important JNK phosphorylation site that is critical for the TNF-α–elicited regulation of γ-secretase. This JNK phosphorylation of PS1 at Ser319Thr320 enhances the stability of the PS1 C-terminal fragment that is necessary for γ-secretase activity. Together, our findings strongly suggest that JNK is a critical intracellular mediator of TNF-α–elicited regulation of γ-secretase and governs the pivotal step in the assembly of functional γ-secretase.

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