Sphingomyelin biosynthesis is essential for phagocytic signaling during mycobacterium tuberculosis host cell entry

Patrick Niekamp, Gaelen Guzman, Hans C. Leier, Ali Rashidfarrokhi, Veronica Richina, Fabian Pott, Caroline Barisch, Joost C.M. Holthuis, Fikadu G. Tafesse

Research output: Contribution to journalArticlepeer-review

Abstract

Phagocytosis by alveolar macrophages is the obligate first step in Mycobacterium tuberculosis (Mtb) infection, yet the mechanism underlying this process is incompletely understood. Here, we show that Mtb invasion relies on an intact sphingolipid biosynthetic pathway. Inhibition or knockout of early sphingolipid bio-synthetic enzymes greatly reduces Mtb uptake across multiple phagocytic cell types without affecting other forms of endocytosis. While the phagocytic receptor dectin-1 undergoes normal clustering at the pathogen contact sites, sphingolipid biosynthetic mutant cells fail to segregate the regulatory phosphatase CD45 from the clustered receptors. Blocking sphingolipid production also impairs downstream activation of Rho GTPases, actin dynamics, and phosphoinositide turnover at the nascent phago-cytic cup. Moreover, we found that production of sphingomyelin, not glycosphingoli-pids, is essential for Mtb uptake. Collectively, our data support a critical role of sphin-gomyelin biosynthesis in an early stage of Mtb infection and provide novel insights into the mechanism underlying phagocytic entry of this pathogen.

Original languageEnglish (US)
Article numbere03141-20
Pages (from-to)1-19
Number of pages19
JournalmBio
Volume12
Issue number1
DOIs
StatePublished - Jan 1 2021

Keywords

  • Cell signaling
  • Mycobacterium tuberculosis
  • Phagocytosis
  • Sphingolipids
  • Sphingomyelin

ASJC Scopus subject areas

  • Microbiology
  • Virology

Fingerprint Dive into the research topics of 'Sphingomyelin biosynthesis is essential for phagocytic signaling during mycobacterium tuberculosis host cell entry'. Together they form a unique fingerprint.

Cite this