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Molecular and Cellular Biology, May 2004, p. 4593-4604, Vol. 24, No. 10
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.10.4593-4604.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Acquisition of Hrs, an Essential Component of Phagosomal Maturation, Is Impaired by Mycobacteria

Otilia V. Vieira,1,{dagger} Rene E. Harrison,1 Cameron C. Scott,1 Harald Stenmark,2 David Alexander,3 Jun Liu,3 Jean Gruenberg,4 Alan D. Schreiber,5 and Sergio Grinstein1*

Cell Biology Program, Hospital for Sick Children, and Department of Biochemistry, University of Toronto, Ontario M5G 1X8,1 Department of Medical Genetics and Microbiology, University of Toronto, Ontario M5S 1A8, Canada,3 Department of Biochemistry, Institute for Cancer Research, Norwegian Radium Hospital, Montebello, and Institute of Pathology, National Hospital, Oslo, Norway,2 Department of Biochemistry, University of Geneva, 1211 Geneva 4, Switzerland,4 Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 191045

Received 8 July 2003/ Returned for modification 4 September 2003/ Accepted 12 February 2004

Pathogenic mycobacteria survive within macrophages by precluding the fusion of phagosomes with late endosomes or lysosomes. Because the molecular determinants of normal phagolysosome formation are poorly understood, the sites targeted by mycobacteria remain unidentified. We found that Hrs, an adaptor molecule involved in protein sorting, associates with phagosomes prior to their fusion with late endosomes or lysosomes. Recruitment of Hrs required the interaction of its FYVE domain with phagosomal phosphatidylinositol 3-phosphate, but two other attachment sites were additionally involved. Depletion of Hrs by use of small interfering RNA impaired phagosomal maturation, preventing the acquisition of lysobisphosphatidic acid and reducing luminal acidification. As a result, the maturation of phagosomes formed in Hrs-depleted cells was arrested at an early stage, characterized by the acquisition and retention of sorting endosomal markers. This phenotype is strikingly similar to that reported to occur in phagosomes of cells infected by mycobacteria. We therefore tested whether Hrs is recruited to phagosomes containing mycobacteria. Hrs associated readily with phagosomes containing inert particles but poorly with mycobacterial phagosomes. Moreover, Hrs was found more frequently in phagosomes containing avirulent Mycobacterium smegmatis than in phagosomes with the more virulent Mycobacterium marinum. These findings suggest that the inability to recruit Hrs contributes to the arrest of phagosomal maturation induced by pathogenic mycobacteria.

* Corresponding author. Mailing address: Division of Cell Biology, Hospital for Sick Children, 555 University Ave., Toronto, Ontario M5G 1X8, Canada. Phone: (416) 813-5727. Fax: (416) 813-5028. E-mail: sga{at}sickkids.on.ca.

{dagger} Present address: Max Planck Institute for Molecular Cell Biology and Genetics, 01307 Dresden, Germany.

Molecular and Cellular Biology, May 2004, p. 4593-4604, Vol. 24, No. 10
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.10.4593-4604.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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