Analysis of the Mechanosensor Channel Functionality of TACAN

Niu, Yiming; Tao, Xiao; Vaisey, George; Olinares, Paul Dominic B.; Alwaseem, Hanan; Chait, Brian T.; MacKinnon, Roderick

doi:10.1101/2021.06.11.448078

Cited by 4 publications

(9 citation statements)

References 40 publications

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“…Although we do not yet know if TMEM-120/TMEM120A acts specifically with one or more enzymes in the TAG synthesis pathway, the ability of purified TMEM120A to bind CoASH is intriguing (Niu et al, 2021;Rong et al, 2021;Xue et al, 2021). This is because fatty acids are converted to fatty acyl-CoA by acyl-CoA synthetases, prior to their addition to the glycerol backbone by a series of acyltransferases (Coleman and Lee, 2004;Yen et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

“…3A). According to its cryo-EM structure, membrane embedded TMEM120A has 6 transmembrane helices and forms homodimers (Ke et al, 2021;Niu et al, 2021;Rong et al, 2021;Xue et al, 2021). Intriguing, a consensus has yet to emerge regarding the subcellular localization of TMEM120A.…”

Section: Tmem-120 Is An Er Resident Proteinmentioning

confidence: 99%

“…S1A). Based on the recently determined structures of TMEM120A, this conserved Glycine residue locates in a flexible linker immediately Nterminal to a coenzyme-A (CoASH) binding site (Niu et al, 2021;Rong et al, 2021;Xue et al, 2021). Therefore, its replacement with Glutamate may alter the conformation of the linker and in turn affect the orientation of residues that constitute the CoASH binding site (including W193 of human TMEM120A and W197 of C. elegans TMEM-120).…”

Section: Tmem-120 Is Required For Tag Accumulation and Ld Expansionmentioning

confidence: 99%

“…More recently, TMEM120A was reported to act at the cell surface as an ion channel that is sensitive to mechanical cues (Beaulieu-Laroche et al, 2020). However, four independent studies did not support such conclusion (Ke et al, 2021;Niu et al, 2021;Rong et al, 2021;Xue et al, 2021). Instead, structural and biochemical analyses indicate that TMEM120A forms a symmetrical homodimer and each protomer binds specifically to a coenzyme-A (CoASH) molecule (Niu et al, 2021;Rong et al, 2021;Xue et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

“…However, four independent studies did not support such conclusion (Ke et al, 2021;Niu et al, 2021;Rong et al, 2021;Xue et al, 2021). Instead, structural and biochemical analyses indicate that TMEM120A forms a symmetrical homodimer and each protomer binds specifically to a coenzyme-A (CoASH) molecule (Niu et al, 2021;Rong et al, 2021;Xue et al, 2021). These observations led to the proposal that TMEM120A has an undefined role in lipid metabolism, which correlates with its requirement for adipogenesis (Batrakou et al, 2015;Czapiewski et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

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The endoplasmic reticulum-resident protein TMEM-120/TMEM120A promotes fat storage in C. elegans and mammalian cells

Huang

et al. 2021

Preprint

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The synthesis of triacylglycerol (TAG) is essential for the storage of excess fatty acids, which can subsequently be used for energy or cell growth. A series of enzymes act in the endoplasmic reticulum (ER) to synthesize TAG, prior to its transfer to lipid droplets (LDs), which are conserved organelles for fat storage. Here, we report that the deficiency of TMEM-120/TMEM120A, a protein with 6-transmembrane helices, retards TAG synthesis and LD expansion in C. elegans. GFP fusion proteins of TMEM-120, expressed at the endogenous level in live worms, were observed throughout the ER network. Using Stimulated Raman Scattering, we demonstrated the specific requirement of TMEM-120 in the storage of exogenous fatty acids in LDs. Knockdown of TMEM120A impedes adipogenesis of pre-adipocytes in vitro, while its over-expression is sufficient to promote LD expansion in mammalian cells. Our results suggest that TMEM-120/TMEM120A plays a conserved role in increasing the efficiency of TAG synthesis.

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Section: Discussionmentioning

confidence: 99%

Section: Tmem-120 Is An Er Resident Proteinmentioning

confidence: 99%

Section: Tmem-120 Is Required For Tag Accumulation and Ld Expansionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The endoplasmic reticulum-resident protein TMEM-120/TMEM120A promotes fat storage in C. elegans and mammalian cells

Huang

et al. 2021

Preprint

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TMEM120A/TACAN inhibits mechanically activated Piezo2 channels

Rosario

Gabrielle

Yudin

et al. 2021

Preprint

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Mechanically activated Piezo2 channels are key mediators of light touch and proprioception in mice and humans. Relatively little is known about what other proteins regulate Piezo2 activity in a cellular context. TACAN (TMEM120A) was proposed to act as a high threshold mechanically activated ion channel in nociceptive dorsal root ganglion (DRG) neurons. Here we find that TACAN co-expression robustly reduced mechanically activated Piezo2 currents, but did not inhibit mechanically activated Piezo1 and TREK1 currents. TACAN co-expression did not affect cell surface expression of either Piezo1 or Piezo2 and did not have major effects on the cortical actin or tubulin cytoskeleton. TACAN expression alone did not result in the appearance of mechanically activated currents above background. In addition, TACAN and Piezo2 expression in DRG neurons overlapped, and siRNA mediated knockdown of TACAN did not decrease the proportion of slowly adapting mechanically activated currents, but resulted in an increased proportion of rapidly adapting currents. Our data do not support TACAN being a mechanically activated ion channel, and identify it as a negative modulator of Piezo2 channel activity.

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The SARS-CoV-2 accessory protein Orf3a is not an ion channel, but does interact with trafficking proteins

Miller

Houlihan

Matamala

et al. 2022

Preprint

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The severe acute respiratory syndrome associated coronavirus 2 (SARS-CoV-2) and SARS-CoV-1 accessory protein Orf3a colocalizes with markers of the plasma membrane, endocytic pathway, and Golgi apparatus. Some reports have led to annotation of both Orf3a proteins as a viroporin. Here we show that neither SARS-CoV-2 nor SARS-CoV-1 form functional ion conducting pores and that the conductances measured are common contaminants in overexpression and with high levels of protein in reconstitution studies. Cryo-EM structures of both SARS-CoV-2 and SARS-CoV-1 Orf3a display a narrow constriction and the presence of a basic aqueous vestibule, which would not favor cation permeation. We observe enrichment of the late endosomal marker Rab7 upon SARS-CoV-2 Orf3a overexpression, and co-immunoprecipitation with VPS39. Interestingly, SARS-CoV-1 Orf3a does not cause the same cellular phenotype as SARS-CoV-2 Orf3a and does not interact with VPS39. To explain this difference, we find that a divergent, unstructured loop of SARS-CoV-2 Orf3a facilitates its binding with VPS39, a HOPS complex tethering protein involved in late endosome and autophagosome fusion with lysosomes. We suggest that the added loop enhances SARS-CoV-2 Orf3a ability to co-opt host cellular trafficking mechanisms for viral exit or host immune evasion.

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Analysis of the Mechanosensor Channel Functionality of TACAN

Cited by 4 publications

References 40 publications

The endoplasmic reticulum-resident protein TMEM-120/TMEM120A promotes fat storage in C. elegans and mammalian cells

The endoplasmic reticulum-resident protein TMEM-120/TMEM120A promotes fat storage in C. elegans and mammalian cells

TMEM120A/TACAN inhibits mechanically activated Piezo2 channels

The SARS-CoV-2 accessory protein Orf3a is not an ion channel, but does interact with trafficking proteins

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