Salmonella Inhibits Retrograde Trafficking of Mannose-6-Phosphate Receptors and Lysosome Function

Kieran McGourty et al.  Science Vol 338 16 November 2012

Speaker: Cheng-Lun Hsu (徐政倫)            Time: 14:00~15:00, May. 22, 2013

Commentator: Dr. Pei-Jane Tsai (蔡佩珍 博士)  Place: Room 601

Abstract:

Salmonella enterica is able to invade and replicate within membrane-bound vacuoles by injecting T3SS effector proteins into host cells. Previous study has shown that the T3SS effector protein, SifA is required for theformation of Salmonella containing vacuoles (SCV), which are rich inlysosomal glycoprotein but reduced in hydrolytic enzymes and mannose-6-phosphate receptors (MPR). MPRs function to deliver lysosomal enzymes from trans-Golgi networks (TGN) to endosome. The author found that SifA subverted retrograde trafficking of MPRs, thereby causing the characteristics of SCVs. Based on quantification of fluorescence signals of TGN-associated CD-MPR or CI-MPR, MPRs were not completely colocalized with TGN46 in wild type Salmonella infection but not ssaV mutant, indicating that redistribution of MPRs requires T3SS. Furthermore, the author proved that leucine 130 residue of SifA was dominated for lowering recycling of MPRs from endosomes to TGNs througth interacting with host protein, SKIP. The author also examined the effect of the interaction between SifA and SKIP on the secretion and activity of lysosomal enzyme,cathepsin B(CatB) and β-hexoraminidase(β-hexo). Results showed that lysosomal enzymes were  misrouted and in loss of activity after wild-type Salmonella infection. Next, the author figureed out that the interaction between SifA and SKIP caused the redistribution of MPRs through interfering Rab9-mediated retrograde trafficking of MPR, and SifA could enhance the dissociation of Rab9 from MPR vesicles. The increased bacteria growth was observed in defective TGN recycling pathway by knockdown of syn10, suggesting that SifA, SKIP and Rab9 form a stable complex to lower recycling of MPRs from lysosome to TGNs. Together, this work demonstrates that the inhibition of retrograde trafficking of MPRs might enhance the intracellular bacteria growth within vacuoles.

References:

1.          Growth and killing of a Salmonella enterica serovar Typhimurium sifA mutant strain in the cytosol of different host cell lines. Carmen R. Beuzon, et al. Microbiology (2002), 148, 2705–2715.

2.          A syntaxin 10 – SNARE complex distinguishes two distinct transport routes from endosomes to the trans-Golgi in human cells. Ian G. Ganley , et al. The Journal of Cell Biology, Vol. 180, No. 1, January 14, 2008 159–172.