Mantegazza Research

López-Haber C., Netting D.J., Hutchins Z., Ma X., Hamilton K.E. and Mantegazza A.R. 2022. "The phagosomal transporter SLC15A4 favors inflammasome activity via mTORC1 signaling and autophagy restraint in dendritic cells". EMBO J. 41(20):e111161.

We show that SLC15A4 promotes inflammasome activity by activating mTORC1 and inhibiting autophagy, a negative regulator of inflammation, both in vitro and in an in vivo model of non-pathogenic colitis.

López Haber C., Levin-Konigsberg R., Karchin J., Zhu Y., Balla T., Grinstein S., Marks M.S. and Mantegazza A.R. 2020. “The lipid kinase Phosphatidylinositol-4-kinase IIα licenses phagosomes for TLR4 signaling and MHC-II presentation in dendritic cells”. Proc. Natl. Acad. Sci. U.S.A. 117(45):28251-28262.

We show that the lipid kinase PI4K2a promotes phagosome autonomous signaling by ensuring the localization of TIRAP and TLR4 to PI4P-enriched platforms. Preserving phagosomal identity and autonomy is essential to differentiate between mild and potent immune responses depending on the encountered threat.

Mantegazza AR, Wynosky-Dolfi M, Casson C, Lefkovith A, Shin S, Brodsky I and Marks MS. 2017. “Increased autophagic sequestration in Adaptor protein-3 deficient dendritic cells limits inflammasome activity and impairs antibacterial immunity”. PLoS Pathogens 13(12): e1006785. 

Our observations demonstrate a link between an endosomal trafficking adaptor (AP-3), the activity of the inflammasome and autophagy, and identify a novel regulator of inflammation. IL-1β and IL-17 deficiency may also explain neutropenia and recurrent bacterial infections in patients deficient in AP-3.

Mantegazza AR, Zajac AL, Twelvetrees A, Holzbaur EL, Amigorena S and Marks   MS. 2014. “TLR-dependent phagosome tubulation in dendritic cells promotes phagosome cross-talk to optimize MHC-II antigen presentation”. Proc. Natl. Acad. Sci. U.S.A. 111(43): 15508-15513. 

We show that the compartmentalization of TLR signaling allows for an additional level of control of the antimicrobial immune response and optimizes MHC-II presentation of phagocytosed antigen to T cells by favoring the transfer of content between TLR signaling phagosomes, to boost and refine the immune response against pathogens.

Mantegazza AR, Guttentag SH, El-Benna J, Sasai M, Iwasaki A, Shen H, Laufer TM and Marks MS. 2012 “Adaptor Protein-3 in Dendritic Cells Facilitates Phagosomal Toll-like Receptor Signaling and Antigen Presentation to CD4(+) T Cells”. Immunity 36(5): 782-794. (Highlighted in:  Nat Rev Immunol. 2012, 12(6): 400).

AP-3 is disabled in the genetic disorder Hermansky-Pudlak syndrome type 2 (HPS2), characterized by immunodeficiency. Our observations of an impaired immune response in the absence of AP-3 contributed to the understanding of HPS2 pathology.