Disruption of Serinc1, which facilitates serine-derived lipid synthesis, fails to alter macrophage function, lymphocyte proliferation or autoimmune disease susceptibility

Chu, Edward; Elso, Colleen M.; Pollock, Abigail H.; Alsayb, May A.; Mackin, Leanne; Thomas, Helen E.; Kay, Thomas W. H.; Silveira, Pablo A.; Mansell, Ashley; Gaus, Katharina; Brodnicki, Thomas C.

doi:10.1016/j.molimm.2016.12.007

Cited by 17 publications

(15 citation statements)

References 74 publications

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“…Serine incorporation by SERINC5 therefore does not seem to contribute to the biosynthesis of these lipids in this experimental system. Similar findings were made recently in a mouse strain in which expression of SER-INC1 is abolished by retroviral insertion but did not affect the composition of serine-derived lipids in lymphocytes and macrophages (64). The fact that no significant changes in cellular SP composition were observed upon manipulation of individual SERINC proteins may reflect compensation of the serine incorporator function by other members of the SERINC pro- experiments) are shown relative to HIV-1 WT particles ϩ control (set to 100%).…”

Section: Discussionsupporting

confidence: 89%

The host-cell restriction factor SERINC5 restricts HIV-1 infectivity without altering the lipid composition and organization of viral particles

Trautz¹,

Wiedemann

Lüchtenborg

et al. 2017

Journal of Biological Chemistry

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The host-cell restriction factor SERINC5 potently suppresses the infectivity of HIV, type 1 (HIV-1) particles, and is counteracted by the viral pathogenesis factor Nef. However, the molecular mechanism by which SERINC5 restricts HIV-1 particle infectivity is still unclear. Because SERINC proteins have been suggested to facilitate the incorporation of serine during the biosynthesis of membrane lipids and because lipid composition of HIV particles is a major determinant of the infectious potential of the particles, we tested whether SERINC5-mediated restriction of HIV particle infectivity involves alterations of membrane lipid composition. We produced and purified HIV-1 particles from SERINC5293T cells with very low endogenous SERINC5 levels under conditions in which ectopically expressed SERINC5 restricts HIV-1 infectivity and is antagonized by Nef and analyzed both virions and producer cells with quantitative lipid MS. SERINC5 restriction and Nef antagonism were not associated with significant alterations in steady-state lipid composition of producer cells and HIV particles. Sphingosine metabolism kinetics were also unaltered by SERINC5 expression. Moreover, the levels of phosphatidylserine on the surface of HIV-1 particles, which may trigger uptake into non-productive internalization pathways in target cells, did not change upon expression of SERINC5 or Nef. Finally, saturating the phosphatidylserine-binding sites on HIV target cells did not affect SERINC5 restriction or Nef antagonism. These results demonstrate that the restriction of HIV-1 particle infectivity by SERINC5 does not depend on alterations in lipid composition and organization of HIV-1 particles and suggest that channeling serine into lipid biosynthesis may not be a cardinal cellular function of SERINC5.

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Section: Discussionsupporting

confidence: 89%

The host-cell restriction factor SERINC5 restricts HIV-1 infectivity without altering the lipid composition and organization of viral particles

Trautz¹,

Wiedemann

Lüchtenborg

et al. 2017

Journal of Biological Chemistry

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“…Meanwhile, defects in Acaa2 and Acox1 increase the risk of renal diseases (16,82). In fact, we found that one of the key genes of serine-derived lipid synthesis, Serinc3, inhibits serine-derived lipid synthesis (83), and we propose that troxerutin relieves lipid accumulation associated with serine in renal tubular epithelial cells. The restoration of energy metabolism is also reflected in the regulatory effects of troxerutin on elevated levels of toxic glucose metabolites, mitochondrial dysfunction, and apoptosisassociated factors, suggesting relief of oxidative stress.…”

Section: Discussionmentioning

confidence: 79%

Precision toxicology shows that troxerutin alleviates ochratoxin A–induced renal lipotoxicity

Yang

Huang

et al. 2018

FASEB j.

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Lipotoxicity is the most common cause of severe kidney disease, with few treatment options available today. Precision toxicology can improve detection of subtle intracellular changes in response to exogenous substrates; thus, it facilitates in‐depth research on bioactive molecules that may interfere with the onset of certain diseases. In the current study, troxerutin significantly relieved nephrotoxicity, increased endurance, and improved systemic energy metabolism and renal inflammation in OTA‐induced nephrotic mice. Lipidomics showed that troxerutin effectively reduced the levels of triglycerides, phosphatidylcholines, and phosphatidylethanolamines in nephropathy. The mechanism was partly attributable to troxerutin in alleviating the aberrantly up‐regulated expression of sphingomyelinase, the cystic fibrosis transmembrane conductance regulator, and chloride channel 2. Renal tubular epithelial cells, the main site of toxin‐induced accumulation of lipids in the kidney, were subjected to transcriptomic profiling, which uncovered several metabolic factors relevant to aberrant lipid and lipoprotein metabolism. Our work provides new insights into the molecular features of toxin‐induced lipotoxicity in renal tubular epithelial cells in vivo and demonstrates the function of troxerutin in alleviating OTA‐induced nephrosis and associated systemic energy metabolism disorders.—Yang, X., Xu, W., Huang, K., Zhang, B., Wang, H., Zhang, X., Gong, L., Luo, Y., He, X. Precision toxicology shows that troxerutin alleviates ochratoxin A‐induced renal lipotoxicity. FASEB J. 33, 2212–2227 (2019). http://www.fasebj.org

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“…Little is known about the function of SERINCs, despite their recent identification as HIV restriction factors 53 – 55 and their high degree of conservation in all branches of eukaryotes. They were originally proposed to mediate the incorporation of serine into membrane lipids 56 , but recent functional studies have shown no effect on membrane composition 57 , 58 . Our discovery that ATG9A and SERINCs are trafficked together suggests a functional relationship.…”

Section: Discussionmentioning

confidence: 99%

AP-4 vesicles contribute to spatial control of autophagy via RUSC-dependent peripheral delivery of ATG9A

et al. 2018

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Adaptor protein 4 (AP-4) is an ancient membrane trafficking complex, whose function has largely remained elusive. In humans, AP-4 deficiency causes a severe neurological disorder of unknown aetiology. We apply unbiased proteomic methods, including ‘Dynamic Organellar Maps’, to find proteins whose subcellular localisation depends on AP-4. We identify three transmembrane cargo proteins, ATG9A, SERINC1 and SERINC3, and two AP-4 accessory proteins, RUSC1 and RUSC2. We demonstrate that AP-4 deficiency causes missorting of ATG9A in diverse cell types, including patient-derived cells, as well as dysregulation of autophagy. RUSC2 facilitates the transport of AP-4-derived, ATG9A-positive vesicles from the trans-Golgi network to the cell periphery. These vesicles cluster in close association with autophagosomes, suggesting they are the “ATG9A reservoir” required for autophagosome biogenesis. Our study uncovers ATG9A trafficking as a ubiquitous function of the AP-4 pathway. Furthermore, it provides a potential molecular pathomechanism of AP-4 deficiency, through dysregulated spatial control of autophagy.

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Disruption of Serinc1, which facilitates serine-derived lipid synthesis, fails to alter macrophage function, lymphocyte proliferation or autoimmune disease susceptibility

Cited by 17 publications

References 74 publications

The host-cell restriction factor SERINC5 restricts HIV-1 infectivity without altering the lipid composition and organization of viral particles

The host-cell restriction factor SERINC5 restricts HIV-1 infectivity without altering the lipid composition and organization of viral particles

Precision toxicology shows that troxerutin alleviates ochratoxin A–induced renal lipotoxicity

AP-4 vesicles contribute to spatial control of autophagy via RUSC-dependent peripheral delivery of ATG9A

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