Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2019 Jan 7:9:1507.
doi: 10.3389/fphar.2018.01507. eCollection 2018.

Regulatory Roles of Sortilin and SorLA in Immune-Related Processes

Hugo Talbot  1 , Sofiane Saada  1 , Thomas Naves  1 , Paul-François Gallet  1 , Anne-Laure Fauchais  1   2 , Marie-Odile Jauberteau  1   3
Affiliations
Review

Regulatory Roles of Sortilin and SorLA in Immune-Related Processes

Hugo Talbot et al. Front Pharmacol. .

Abstract

Sortilin, also known as Neurotensin Receptor-3, and the sorting-related receptor with type-A repeats (SorLA) are both members of the Vps10p domain receptor family. Initially identified in CNS cells, they are expressed in various other cell types where they exert multiple functions. Although mostly studied for its involvement in Alzheimer's disease, SorLA has recently been shown to be implicated in immune response by regulating IL-6-mediated signaling, as well as driving monocyte migration. Sortilin has been shown to act as a receptor, as a co-receptor and as an intra- and extracellular trafficking regulator. In the last two decades, deregulation of sortilin has been demonstrated to be involved in many human pathophysiologies, including neurodegenerative disorders (Alzheimer and Parkinson diseases), type 2 diabetes and obesity, cancer, and cardiovascular pathologies such as atherosclerosis. Several studies highlighted different functions of sortilin in the immune system, notably in microglia, pro-inflammatory cytokine regulation, phagosome fusion and pathogen clearance. In this review, we will analyze the multiple roles of sortilin and SorLA in the human immune system and how their deregulation may be involved in disease development.

Keywords: SorLA; cytokines; immune system; inflammation; phagocytosis; signaling; sortilin; trafficking.

PubMed Disclaimer

Figures

FIGURE 1
FIGURE 1
Role of Vps10p domain receptors in intracellular protein trafficking. (A) Schematic representation of sortilin and SorLA protein domains. (B) Trafficking pathways of Vps10p domain receptors. The propeptide is cleaved by pro-protein convertases in the trans Golgi network (step 1). Vps10p domain receptors associated with a protein partner can then be secreted from the TGN to extracellular vesicles through secretory granules (step 2) or addressed to the plasma membrane via constitutive secretory vesicles. Partners can either be anchored to the membrane or secreted as soluble proteins (steps 3–4). Once anchored to the membrane, Vps10p domain receptors can undergo proteolytic cleavage by a disintegrin and metalloprotease (ADAM) 10 or ADAM17, followed by γ-secretase, and be released under a soluble form (step 5). They can mediate internalization of partners from the plasma membrane through AP-2/clathrin-dependent endocytosis (step 6). They can navigate, alone or with partners, between early endosomes and the TGN via the retromer complex (step 7) or anterograde transport via interaction with GCAs/AP-1 (step 8). Early endosomes mature into late endosomes or multi-vesicular bodies (step 9). From there, Vps10p domain receptors and their partners can either be addressed to the lysosome for degradation (step 10) or exocytized in exosomes (step 11).
FIGURE 2
FIGURE 2
Sortilin and SorLA regulate IL-6 family signaling. (A) CNTF binds to CNTFRα, this complex engages the heterodimer gp130/LIFRβ to induce JAK/STAT pathway signaling. Sortilin can bind to LIFRβ and enhance this JAK/STAT signaling. Sortilin also mediates soluble CNTF cellular uptake, and decreases associated signaling. (B) SorLA interacts with CLF-1. CLF-1 can form a complex with CLC and CNTFRα. If this complex is soluble, SorLA binds to CLF-1 and concentrates the complex on the membrane, enhancing interaction with gp130/LIFRβ and JAK/STAT signaling. If this complex is anchored to the membrane, SorLA binds to CLF-1 and mediates endocytosis of the complex, followed by its degradation, decreasing associated signaling. (C) SorLA can bind to IL-6 or IL-6R. Binding of IL-6 to membrane anchored IL-6R, in association with gp130 homodimer, induces cis signaling (JAK/STAT pathway). SorLA can bind IL-6R and inhibits IL-6 binding and subsequent signaling. IL-6 can also engage soluble IL-6R, associated with gp130 homodimer, and induce trans signaling (NF-kB pathway). SorLA may bind to soluble IL-6 and act as a stabilizer, enhancing IL-6 half-life, and thus trans signaling. Additionally, SorLA negatively controls IL-6 turnover by binding to IL-6 or sIL-6R and mediating their endocytosis, followed by lysosomal degradation.
FIGURE 3
FIGURE 3
In macrophages, sortilin is implicated in antigen scavenging and phagosome maturation. (A) Sortilin and scavenger receptor CD206 are addressed from the TGN to the plasma membrane. In Alternatively Associated Macrophages (AAMs), sortilin can bind extracellular antigens and mediate their endocytosis. Antigens are then degraded in the lysosome, and AAMs being incapable of antigen processing, antigen peptides are not presented to T cells by class 2 MHC. (B) Upon phagocytosis of mycobacteria by macrophages, NF-kB pathway is activated, inducing SORT1 transcription. Sortilin is then transported and vehicles Acid Sphingomyelinase, to early phagosomes. This step is crucial to phagosome maturation and mycobacteria growth arrest and degradation.
FIGURE 4
FIGURE 4
Implications of sortilin (A) and SorLA (B) in immune-related processes. Blue circles represent cellular models expressing sortilin or SorLA. Blank circles represent pathways/processes/proteins modified by sortilin or SorLA. Red circles represent physiological or pathological processes induced. Green arrows mean a stimulating role, while red arrows mean an inhibition. The red arrow with a black cross means that the inhibition is lifted.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Ai D., Baez J. M., Jiang H., Conlon D. M., Hernandez-Ono A., Frank-Kamenetsky M., et al. (2012). Activation of ER stress and mTORC1 suppresses hepatic sortilin-1 levels in obese mice. J. Clin. Invest. 122 1677–1687. 10.1172/JCI61248 - DOI - PMC - PubMed
    1. Andersen O. M., Reiche J., Schmidt V., Gotthardt M., Spoelgen R., Behlke J., et al. (2005). Neuronal sorting protein-related receptor sorLA/LR11 regulates processing of the amyloid precursor protein. Proc. Natl. Acad. Sci. U.S.A. 102 13461–13466. 10.1073/pnas.0503689102 - DOI - PMC - PubMed
    1. Aravalli R. N., Peterson P. K., Lokensgard J. R. (2007). Toll-like receptors in defense and damage of the central nervous system. J. Neuroimmune Pharmacol. 2 297–312. 10.1007/s11481-007-9071-5 - DOI - PubMed
    1. Arrant A. E., Onyilo V. C., Unger D. E., Roberson E. D. (2018). Progranulin gene therapy improves lysosomal dysfunction and microglial pathology associated with frontotemporal dementia and neuronal ceroid lipofuscinosis. J. Neurosci. 38 2341–2358. 10.1523/JNEUROSCI.3081-17.2018 - DOI - PMC - PubMed
    1. Blasi F., Carmeliet P. (2002). uPAR: a versatile signalling orchestrator. Nat. Rev. Mol. Cell Biol. 3 932–943. 10.1038/nrm977 - DOI - PubMed

LinkOut - more resources