Unc119 protects from Shigella infection by inhibiting the Abl family kinases.
BACKGROUND
Bacteria engage cell surface receptors and intracellular signaling molecules to enter the cell. Unc119 is an adaptor protein, which interacts with receptors and tyrosine kinases. Its role in bacterial invasion of cells is unknown.


RESULTS
We used biochemical, molecular and cell biology approaches to identify the binding partners of Unc119, and to study the effect of Unc119 on Abl family kinases and Shigella infection. We employed loss-of-function and gain-in-function approaches to study the effect of Unc119 in a mouse model of pulmonary shigellosis. Unc119 interacts with Abl family kinases and inhibits their kinase activity. As a consequence, it inhibits Crk phosphorylation, which is essential for Shigella infection. Unc119 co-localizes with Crk and Shigella in infected cells. Shigella infectivity increases in Unc119-deficient epithelial and macrophage cells. In a mouse model of shigellosis cell-permeable TAT-Unc119 inhibits Shigella infection. Conversely, Unc119 knockdown in vivo results in enhanced bacterial invasion and increased lethality. Unc119 is an inducible protein. Its expression is upregulated by probacteria and bacterial products such as lipopolysacharide and sodium butyrate. The latter inhibits Shigella infection in mouse lungs but is ineffective in Unc119 deficiency.


CONCLUSIONS
Unc119 inhibits signaling pathways that are used by Shigella to enter the cell. As a consequence it provides partial but significant protection from Shigella infections. Unc119 induction in vivo boosts host defense against infections.
Vepachedu
Ramarao
R
National Jewish Health, Denver, CO, USA.
Karim
Zunayet
Z
Patel
Ojas
O
Goplen
Nicholas
N
Alam
Rafeul
R
D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D004195:Disease Models, Animal; D004405:Dysentery, Bacillary / Q000517:prevention & control*; D004789:Enzyme Activation; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D051379:Mice; D008856:Microscopy, Fluorescence; D008868:Microtubule Proteins / Q000502:physiology*; D011494:Protein Kinases / Q000737:chemistry / Q000378:metabolism*; D034741:RNA, Small Interfering
D048868:Adaptor Proteins, Signal Transducing; D047908:Intracellular Signaling Peptides and Proteins; D008868:Microtubule Proteins; D034741:RNA, Small Interfering; C489115:Unc119 protein, mouse; D011494:Protein Kinases