Trends in Immunology

Trends in Immunology

Volume 41, Issue 2, February 2020, Pages 157-171
Journal home page for Trends in Immunology

Review
Key Roles of MiT Transcription Factors in Innate Immunity and Inflammation

https://doi.org/10.1016/j.it.2019.12.003Get rights and content

Highlights

  • TFEB, TFE3, and related MiT TFs are broadly expressed in mammals.

  • Under resting or homeostatic conditions, TFEB and TFE3 reside in the cytosol; their activation entails nuclear translocation, which is triggered by many distinct stimuli.

  • Recently identified upstream regulation of TFEB and/or TFE3 in innate immune cells includes phagocytosis, lysosome damage, IFN-γ, LPS, and extracellular ATP.

  • Recently identified downstream functions of TFEB and/or TFE3 in innate immune cells include autophagy and lysosomal biogenesis, bacterial killing, proinflammatory cytokine production, macrophage classical activation, antiviral responses, and dendritic cell migration.

  • Multiple feedback loops control TFEB and TFE3, mandating sophisticated approaches to safely control their activities for therapeutic purposes.

Microphthalmia/TFE (MiT) transcription factors (TFs), such as transcription factor EB (TFEB) and transcription factor E3 (TFE3), are emerging as key regulators of innate immunity and inflammation. Rapid progress in the field requires a focused update on the latest advances. Recent studies show that TFEB and TFE3 function in innate immune cells to regulate antibacterial and antiviral responses downstream of phagocytosis, interferon (IFN)-γ, lipopolysaccharide (LPS), and adenosine receptors. Moreover, overexpression of TFEB or TFE3 can drive inflammation in vivo, such as in atherosclerosis, while in other scenarios they can perform anti-inflammatory functions. MiT factors may constitute potential therapeutic targets for a broad range of diseases; however, to harness their therapeutic potential, sophisticated ways to manipulate MiT factor activity safely and effectively must be developed.

Section snippets

MiT Factors Regulate Innate Immunity

Transcription of pro- and anti-inflammatory genes in the innate immune system is tightly regulated. Appropriate induction of gene expression occurs during infection or injury and is essential for organismal homeostasis and innate immunity. Inappropriate gene expression can drive inflammation, autoimmune disease, and oncogenesis [1,2]. Thus, an assessment of the TFs that regulate innate immunity and inflammation is essential for understanding homeostasis and pathogenesis.

The MiT family of TFs

Novel Regulatory Mechanisms Upstream of MiT Factors in Innate Immune Cells

Overall, two major inputs are known to regulate TFEB and TFE3 in a range of cell types and organisms (Figure 1). First, mechanistic target of rapamycin, complex 1 (mTORC1) is a negative regulator that phosphorylates conserved Ser/Thr residues on both factors [10,16., 17., 18.]. Such phosphorylation enables 14-3-3 protein binding, which restricts TFEB and TFE3 to the cytosol [16]. Second, protein phosphatase 3 (calcineurin) is the most important enzyme that removes mTORC1-mediated

Lysosome and/or Autophagy Enhancement

The activation of autophagy and lysosomal genes by TFEB in macrophages was first demonstrated in primary PMs from TfebLysM-OX transgenic mice overexpressing TFEB in the myeloid compartment [34]. Compared with WT controls, TfebLysM-OX PMs exhibited an eightfold induction of Tfeb and 1.5- to threefold induction of the TFEB target genes Sqstm1, Lamp1, and Map1lc3b via qRT-PCR [34]. In addition, Tfeb overexpression ameliorated the loss of lysosomes caused by cholesterol crystals, compared with WT

Concluding Remarks

The emerging picture is that TFEB and TFE3 can modulate innate immunity and inflammation by direct mechanisms, controlling the transcription of inflammatory mediators (Figure 2A) and by indirect mechanisms, controlling cellular processes (e.g., metabolism, autophagy, and secretion) that impact microbial infection, organismal metabolism, and inflammatory signaling both locally and systemically (Figure 2B). The large number of cellular processes under TFEB control, as well as the many feedback

Acknowledgments

The author apologizes to researchers whose work was not cited or cited through reviews owing to space limitations. Three anonymous reviewers provided generous feedback and intellectual input. Funding for the Irazoqui laboratory was provided by NSF IOS 1457055, NIH GM101056, and NIH DK043351.

Glossary

Acute respiratory distress syndrome
rapidly progressive pulmonary inflammation.
ADF neurons
sensory C. elegans neurons.
Anti-inflammatory polarized state
macrophage activation causing secretion of proresolution, anti-inflammatory molecules.
ASI neurons
sensory C. elegans neurons.
Autophagy
commonly refers to macroautophagy, in which cells form double-membrane vesicles around portions of the cytosol, which may contain organelles, protein aggregates, or pathogens for lysosomal degradation.
Bleomycin
fungal

References (72)

  • H. Feng

    Conserved domains subserve novel mechanisms and functions in DKF-1, a Caenorhabditis elegans protein kinase D

    J. Biol. Chem.

    (2006)
  • A. Ghosh

    Activation of peroxisome proliferator-activated receptor α induces lysosomal biogenesis in brain cells: implications for lysosomal storage disorders

    J. Biol. Chem.

    (2015)
  • S.T. Smale et al.

    Transcriptional control of inflammatory responses

    Cold Spring Harb. Perspect. Biol.

    (2014)
  • R. Medzhitov et al.

    Transcriptional control of the inflammatory response

    Nat. Rev. Immunol.

    (2009)
  • R.M. Perera

    MiT/TFE family of TFs, lysosomes, and cancer

    Annu. Rev. Cancer Biol.

    (2018)
  • M. Sardiello

    A gene network regulating lysosomal biogenesis and function

    Science

    (2009)
  • C. Settembre

    TFEB links autophagy to lysosomal biogenesis

    Science

    (2011)
  • C. Settembre

    TFEB controls cellular lipid metabolism through a starvation-induced autoregulatory loop

    Nat. Cell Biol.

    (2013)
  • J.A. Martina

    Novel roles for the MiTF/TFE family of TFs in organelle biogenesis, nutrient sensing, and energy homeostasis

    Cell. Mol. Life Sci.

    (2014)
  • J.A. Martina

    The nutrient-responsive transcription factor TFE3 promotes autophagy, lysosomal biogenesis, and clearance of cellular debris

    Sci. Signal.

    (2014)
  • R. Puertollano

    The complex relationship between TFEB transcription factor phosphorylation and subcellular localization

    EMBO J.

    (2018)
  • N. Raben et al.

    TFEB and TFE3: linking lysosomes to cellular adaptation to stress

    Annu. Rev. Cell Dev. Biol.

    (2015)
  • G. Napolitano et al.

    TFEB at a glance

    J. Cell Sci.

    (2016)
  • N. Nabar et al.

    The transcription factor EB links cellular stress to the immune response

    Yale J. Biol. Med.

    (2017)
  • O.A. Brady

    Emerging roles for TFEB in the immune response and inflammation

    Autophagy

    (2017)
  • A. Roczniak-Ferguson

    The transcription factor TFEB links mTORC1 signaling to transcriptional control of lysosome homeostasis

    Sci. Signal.

    (2012)
  • C. Settembre

    A lysosome-to-nucleus signalling mechanism senses and regulates the lysosome via mTOR and TFEB

    EMBO J.

    (2012)
  • J.A. Martina

    MTORC1 functions as a transcriptional regulator of autophagy by preventing nuclear transport of TFEB

    Autophagy

    (2012)
  • D.L. Medina

    Lysosomal calcium signalling regulates autophagy through calcineurin and TFEB

    Nat. Cell Biol.

    (2015)
  • H. Li

    Interaction of calcineurin with substrates and targeting proteins

    Trends Cell Biol.

    (2011)
  • S. Paola

    TRPML1: the Ca(2+)retaker of the lysosome

    Cell Calcium

    (2018)
  • M. Wu

    Immunomodulators targeting MARCO expression improve resistance to postinfluenza bacterial pneumonia

    Am. J. Physiol. Lung Cell Mol. Physiol.

    (2017)
  • N. Singh

    Antimycobacterial effect of IFNG (interferon gamma)-induced autophagy depends on HMOX1 (heme oxygenase 1)-mediated increase in intracellular calcium levels and modulation of PPP3/calcineurin-TFEB (transcription factor EB) axis

    Autophagy

    (2018)
  • S. Brubaker

    Innate immune pattern recognition: a cell biological perspective

    Annu. Rev. Immunol.

    (2015)
  • N. Pastore

    TFEB and TFE3 cooperate in the regulation of the innate immune response in activated macrophages

    Autophagy

    (2016)
  • A. Vural

    Activator of G-protein signaling 3-induced lysosomal biogenesis limits macrophage intracellular bacterial infection

    J. Immunol.

    (2016)

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