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SLIT2/ROBO1 signaling suppresses mTORC1 for organelle control and bacterial killing. | LitMetric

AI Article Synopsis

  • SLIT/ROBO signaling is crucial for regulating cell growth and various functions in immune cells, particularly phagocytes.
  • Recent research reveals that SLIT2 activates ROBO1, which inhibits mTORC1 activity in macrophages, enhancing lysosome formation and promoting autophagy for effective bacterial killing.
  • Disruption of SLIT-ROBO signaling in cancer cells leads to increased mTORC1 activity and reduced autophagy, highlighting SLIT2's role in both immune response and cancer cell survival.

Article Abstract

SLIT/ROBO signaling impacts many aspects of tissue development and homeostasis, in part, through the regulation of cell growth and proliferation. Recent studies have also linked SLIT/ROBO signaling to the regulation of diverse phagocyte functions. However, the mechanisms by which SLIT/ROBO signaling acts at the nexus of cellular growth control and innate immunity remain enigmatic. Here, we show that SLIT2-mediated activation of ROBO1 leads to inhibition of mTORC1 kinase activity in macrophages, leading to dephosphorylation of its downstream targets, including transcription factor EB and ULK1. Consequently, SLIT2 augments lysosome biogenesis, potently induces autophagy, and robustly promotes the killing of bacteria within phagosomes. Concordant with these results, we demonstrate decreased lysosomal content and accumulated peroxisomes in the spinal cords of embryos from , double knockout mice. We also show that impediment of auto/paracrine SLIT-ROBO signaling axis in cancer cells leads to hyperactivation of mTORC1 and inhibition of autophagy. Together, these findings elucidate a central role of chemorepellent SLIT2 in the regulation of mTORC1 activity with important implications for innate immunity and cancer cell survival.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10264968PMC
http://dx.doi.org/10.26508/lsa.202301964DOI Listing

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