Phosphorylation of SNX27 by MAPK11/14 links cellular stress–signaling pathways with endocytic recycling

Mao, Lejiao; Liao, Chenyi; Qin, Jiao; Gong, Yanqiu; Zhou, Yifei; Li, Shasha; Liu, Zhe; Deng, Huaqing; Deng, Wankun; Sun, Qingxiang; Mo, Xianming; Xue, Yu; Billadeau, Daniel D.; Dai, Lunzhi; Li, Guohui; Jia, Da

doi:10.1083/jcb.202010048

Cited by 31 publications

(22 citation statements)

References 70 publications

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“…These results suggest that the correct assembly of the SNX27-retromer complex together with its cargoes is required for its synaptic recruitment. This is further supported by a recent publication showing that impaired cargo recognition by SNX27 reduces retromer targeting to the plasma membrane ( 45 ).…”

Section: Resultssupporting

confidence: 58%

Sorting Nexin 27 Enables MTOC and Secretory Machinery Translocation to the Immune Synapse

et al. 2022

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Sorting nexin 27 (SNX27) association to the retromer complex mediates intracellular trafficking of cargoes containing PSD95/Dlg1/ZO-1 (PDZ)-binding C-terminal sequences from endosomes to the cell surface, preventing their lysosomal degradation. Antigen recognition by T lymphocyte leads to the formation of a highly organized structure named the immune synapse (IS), which ensures cell-cell communication and sustained T cell activation. At the neuronal synapse, SNX27 recycles PDZ-binding receptors and its defective expression is associated with synaptic dysfunction and cognitive impairment. In T lymphocytes, SNX27 was found localized at recycling endosomal compartments that polarized to the IS, suggesting a function in polarized traffic to this structure. Proteomic analysis of PDZ-SNX27 interactors during IS formation identify proteins with known functions in cytoskeletal reorganization and lipid regulation, such as diacylglycerol (DAG) kinase (DGK) ζ, as well as components of the retromer and WASH complex. In this study, we investigated the consequences of SNX27 deficiency in cytoskeletal reorganization during IS formation. Our analyses demonstrate that SNX27 controls the polarization towards the cell-cell interface of the PDZ-interacting cargoes DGKζ and the retromer subunit vacuolar protein sorting protein 26, among others. SNX27 silencing abolishes the formation of a DAG gradient at the IS and prevents re-localization of the dynactin complex component dynactin-1/p150Glued, two events that correlate with impaired microtubule organizing center translocation (MTOC). SNX27 silenced cells show marked alteration in cytoskeleton organization including a failure in the organization of the microtubule network and defects in actin clearance at the IS. Reduced SNX27 expression was also found to hinder the arrangement of signaling microclusters at the IS, as well as the polarization of the secretory machinery towards the antigen presenting cells. Our results broaden the knowledge of SNX27 function in T lymphocytes by showing a function in modulating IS organization through regulated trafficking of cargoes.

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Section: Resultssupporting

confidence: 58%

Sorting Nexin 27 Enables MTOC and Secretory Machinery Translocation to the Immune Synapse

et al. 2022

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“…As one of the most notorious infectious diseases the modern human history, the novel coronavirus 2019 (COVID- 19) has infected at least 200 million individuals, as of August dysfunction, and even death within a short period. [1][2][3] SARS-CoV-2 enters host cells through two distinct pathways: fusion at the plasma membrane or endocytosis.…”

Section: Introductionmentioning

confidence: 99%

“…14,17,18 SNX27 harbors a PDZ domain, which can bind to the PDZ-binding -motif (PDZbm) presented in the cytoplasmic tails of many membrane proteins, including the glucose transporter GLUT1 and many G-protein-coupled receptors, and promotes their endosome-to-plasma membrane recycling. 14,19 In addition to angiotensin-converting enzyme 2 (ACE2), the surface receptor for S protein, SARS-CoV-2 infection requires dozens of host factors. Whole genome CRISPR screens have identified that endocytic trafficking regulators, such as SNX27 and retromer, are required for SARS-CoV-2 infection.…”

Section: Introductionmentioning

confidence: 99%

SARS‐CoV‐2 spike protein harnesses SNX27‐mediated endocytic recycling pathway

Zhao

Zhong

Zhao

et al. 2021

MedComm

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SARS-CoV-2 is an enveloped positive-sense RNA virus that depends on host factors for all stages of its life. Membrane receptor ACE2 is a well-established factor for SARS-CoV-2 docking. In addition to ACE2, whole-genome genetic screens have identified additional proteins, such as endosomal trafficking regulators SNX27 and retromer, as key host factors required for SARS-CoV-2 infection. However, it is poorly understood how SARS-CoV-2 utilize host endocytic transport pathways to produce productive infection. Here, we report that SNX27 interacts with the SARS-CoV-2 spike (S) protein to facilitate S protein surface expression. Interestingly, S protein binds to the PDZ domain of SNX27, although it does not contain a PDZ-binding motif (PDZbm). Either abrogation of the SNX27 PDZ domain or S protein "MTSC" motif, which is critical for SNX27 binding, decreases surface expression of S protein and viral production. Collectively, our study highlights a novel approach utilized by SARS-CoV-2 to facilitate virion trafficking to establish virus infection.

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“…A well characterized example of cargo tail phosphorylation modulating SNX27 affinity and subsequent endosomal sorting is the β2AR (Cao et al, 1999;Clairfeuille et al, 2016). Furthermore, phosphorylation of SNX27 at Ser-51 alters the conformation of its PDZbm-binding pocket decreasing the affinity for cargo proteins, thereby inhibiting endosomal sorting (Mao et al, 2021) and Ser-302 and Ser-304 phosphorylation in VPS26B can modulate SNX27 association (Wang et al, 2021). Similarly, ESCPE-1 function can be regulated by phosphorylation, in this case Ser-226 of SNX5 undergoes phosphorylation which decreases dimerization with SNX1 and SNX2 and reduces endosomal recycling (Itai et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

Mechanistic basis for SNX27-Retromer coupling to ESCPE-1 in promoting endosomal cargo recycling

Simonetti

Guo

Giménez-Andrés

et al. 2021

Preprint

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Sorting nexin-27 (SNX27)-Retromer is an endosomal sorting complex that orchestrates endosome-to-plasma membrane recycling of hundreds of internalized receptors, channels and transporters, enzymes and adhesion molecules. While SNX27-Retromer is essential for development, subtle functional defects are observed in human disease, most notably neurodegenerative and neurological disorders. Achieving a thorough mechanistic dissection of SNX27-Retromer is central to understanding endosomal sorting in health and disease. Here we combine biochemical, structural and cellular analyses to establish the mechanistic basis through which SNX27-Retromer couples to the membrane tubulating ESCPE-1 complex (Endosomal SNX-BAR sorting complex for promoting exit 1). We show that a conserved surface in the FERM (4.1/ezrin/radixin/moesin) domain of SNX27 directly binds acidic-Asp-Leu-Phe (aDLF) motifs in the disordered amino-termini of the SNX1 and SNX2 subunits of ESCPE-1. This interaction hands-over SNX27-Retromer captured integral membrane proteins into ESCPE-1 tubular profiles to promote their cell surface recycling. Through phylogenetic analysis, we reveal that SNX27:Retromer:ESCPE-1 assembly evolved in a stepwise manner during the early evolution of metazoans, which reflects the increasing complexity of endosomal sorting from the ancestral opisthokont to modern animals.

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Phosphorylation of SNX27 by MAPK11/14 links cellular stress–signaling pathways with endocytic recycling

Cited by 31 publications

References 70 publications

Sorting Nexin 27 Enables MTOC and Secretory Machinery Translocation to the Immune Synapse

Sorting Nexin 27 Enables MTOC and Secretory Machinery Translocation to the Immune Synapse

SARS‐CoV‐2 spike protein harnesses SNX27‐mediated endocytic recycling pathway

Mechanistic basis for SNX27-Retromer coupling to ESCPE-1 in promoting endosomal cargo recycling

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