ESCRT (endosomal complexes required for transport) proteins can repair plasma membrane wounds caused by toxins and mechanical damage. Ritter et al. showed that during the process of lysis by CTLs, tumor cell ESCRT proteins localized to the cytolytic synapse. Impairment of ESCRT function (either by CRISPR KO of an ESCRT protein or by overexpression of a dominant-negative kinase allele) rendered targets more susceptible to killing, an observation repeated over a broad range of target–TCR affinities. ESCRT-impaired targets were also more susceptible to killing by exposure to combined perforin and granzyme.
Contributed by Margot O’Toole
ABSTRACT: Cytotoxic T lymphocytes (CTLs) and natural killer cells kill virus-infected and tumor cells through the polarized release of perforin and granzymes. Perforin is a pore-forming toxin that creates a lesion in the plasma membrane of the target cell through which granzymes enter the cytosol and initiate apoptosis. Endosomal sorting complexes required for transport (ESCRT) proteins are involved in the repair of small membrane wounds. We found that ESCRT proteins were precisely recruited in target cells to sites of CTL engagement immediately after perforin release. Inhibition of ESCRT machinery in cancer-derived cells enhanced their susceptibility to CTL-mediated killing. Thus, repair of perforin pores by ESCRT machinery limits granzyme entry into the cytosol, potentially enabling target cells to resist cytolytic attack.
Author Info: (1) Genentech, Inc., South San Francisco, CA 94080, USA. (2) Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147, USA. (3) Janelia Research Campus, Howard H
Author Info: (1) Genentech, Inc., South San Francisco, CA 94080, USA. (2) Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147, USA. (3) Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147, USA. (4) Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147, USA. (5) Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147, USA. (6) Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147, USA. (7) Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147, USA. (8) Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147, USA. (9) Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147, USA. (10) Rosie Lew Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne VIC, Australia. (11) Rosie Lew Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne VIC, Australia. (12) Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147, USA. (13) Genentech, Inc., South San Francisco, CA 94080, USA.
