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Blood, 1 December 2001, Vol. 98, No. 12, pp. 3429-3434
PHAGOCYTES
The cytoplasmic domain of Fc RIIA
(CD32) participates in phagolysosome
formation
Randall G. Worth,
Laura Mayo-Bond,
Moo-Kyung Kim,
Jan G. J. van de
Winkel,
Robert F. Todd III,
Howard R. Petty, and
Alan D. Schreiber
From the Department of Biological Sciences, Wayne State
University, Detroit, MI; Division of Hematology and Oncology,
University of Michigan School of Medicine, Ann Arbor, MI; Department of
Immunotherapy, Medarex Europe, University Medical Center, Utrecht, The
Netherlands; and Division of Hematology and Oncology, University of
Pennsylvania School of Medicine, Philadelphia, PA.
Signaling motifs located within the cytoplasmic domain of certain
receptors contribute to lysosome fusion. Most studies have described
lysosome fusion with respect to endocytic receptors. Phagolysosome
fusion has not been extensively studied. To test the hypothesis that
the tail of Fc RIIA participates in phagolysosomal fusion, a
"reverse" genetic complementation system was used. It was
previously shown that complement receptor type 3 (CR3) can rescue the
phagocytic activity of a mutant FcRIIA lacking its cytoplasmic
domain (tail-minus form). This system has allowed us to study Fc
receptor-dependent phagocytosis and phagolysosome fusion in the
presence and absence of the cytoplasmic domain of FcRIIA.
Fluorescent dextran was used to label lysosomes. After target
internalization, wild-type FcRIIA-mediated phagolysosome formation was observed as indicated by colocalization of fluorescent dextran and the phagosome. In addition, when studying mutants of
FcRIIA containing a full-length cytoplasmic tail with the 2 ITAM
tyrosines mutated to phenylalanine, (1) phagocytosis was abolished, (2)
CR3 restored phagocytosis, and (3) lysosomal fusion was similar to that
observed with the wild-type receptor. In contrast, in the presence of
CR3 and the tail-minus form of FcRIIA, internalized particles did
not colocalize with dextran. Electron microscopy revealed that the
lysosomal enzyme acid phosphatase colocalized with immunoglobulin
G-coated targets internalized by wild-type FcRIIA but not by
tail-minus FcRIIA and CR3. Thus, the tail of FcRIIA contributes
to phagolysosome fusion by a mechanism that does not require a
functional ITAM sequence.
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