8.A.179.  The Novel Acetylcholine Receptor Chaperone (NACHO) Family

NACHO (TMEM35A) is a molecular chaperone that mediates the proper assembly and functional expression of nicotinic acetylcholine receptors (nAChRs) throughout the brain (Gu et al. 2016, Rex et al. 2017, Kweon et al. 2020). It is essential for the proper folding, assembly, function and surface trafficking of alpha-7 (CHRNA7), alpha-4-beta-2, alpha-3-beta-2 and alpha-3-beta-4 receptors (Gu et al. 2016, , Matta et al. 2017, Deshpande et al. 2020, Kweon et al. 2020). It  stably associates with ribophorin-1 (RPN1) and ribophorin-2 (RPN2) (components of the oligosaccharyl transferase (OST) complex; TC# 9.B.142.3.17) and with calnexin (CANX; TC# 8.A.165), all of which are critical for NACHO-mediated effects on CHRNA7 assembly and function. NACHO facilitates the proper folding and assembly of alpha-6-beta-2 and alpha-6-beta-2-beta-3 receptors and acts at early stages of the nAChRs subunit assembly (Matta et al. 2017). It promotes the expression of the alpha-42:beta-23 stoichiometric form over the alpha-43:beta-22 form (Mazzaferro et al. 2021).

 

 

 


 

References:

Deshpande, A., R.M. Vinayakamoorthy, B.K. Garg, J.P. Thummapudi, G. Oza, K. Adhikari, A. Agarwal, P. Dalvi, S. Iyer, S. Thulasi Raman, V. Ramesh, A. Rameshbabu, A. Rezvaya, S. Sukumaran, S. Swaminathan, B. Tilak, Z. Wang, P.V. Tran, and R.H. Loring. (2020). Why Does Knocking Out NACHO, But Not RIC3, Completely Block Expression of α7 Nicotinic Receptors in Mouse Brain? Biomolecules 10:.
Gu, S., J.A. Matta, B. Lord, A.W. Harrington, S.W. Sutton, W.B. Davini, and D.S. Bredt. (2016). Brain α7 Nicotinic Acetylcholine Receptor Assembly Requires NACHO. Neuron. 89: 948-955.
Hoffman, J.L., S. Faccidomo, B.L. Saunders, S.M. Taylor, M. Kim, and C.W. Hodge. (2021). Inhibition of AMPA receptors (AMPARs) containing transmembrane AMPAR regulatory protein γ-8 with JNJ-55511118 shows preclinical efficacy in reducing chronic repetitive alcohol self-administration. Alcohol Clin Exp Res 45: 1424-1435.
Kweon, H.J., S. Gu, E. Witham, M. Dhara, H. Yu, E.D. Mandon, A. Jawhari, and D.S. Bredt. (2020). NACHO Engages N-Glycosylation ER Chaperone Pathways for α7 Nicotinic Receptor Assembly. Cell Rep 32: 108025.
Loring, R.H. (2022). Speculation on How RIC-3 and Other Chaperones Facilitate α7 Nicotinic Receptor Folding and Assembly. Molecules 27:.
Ma, X., M. Li, G. Lu, R. Wang, Y. Wei, Y. Guo, Y. Yu, and C. Jiang. (2021). Anti-inflammation of epicatechin mediated by TMEM35A and TMPO in bovine mammary epithelial cell line cells and mouse mammary gland. J Dairy Sci 104: 12925-12938.
Matta, J.A., S. Gu, W.B. Davini, B. Lord, E.R. Siuda, A.W. Harrington, and D.S. Bredt. (2017). NACHO Mediates Nicotinic Acetylcholine Receptor Function throughout the Brain. Cell Rep 19: 688-696.
Mazzaferro, S., S.T. Whiteman, C. Alcaino, A. Beyder, and S.M. Sine. (2021). NACHO and 14-3-3 promote expression of distinct subunit stoichiometries of the α4β2 acetylcholine receptor. Cell Mol Life Sci 78: 1565-1575.
Rex, E.B., N. Shukla, S. Gu, D. Bredt, and D. DiSepio. (2017). A Genome-Wide Arrayed cDNA Screen to Identify Functional Modulators of α7 Nicotinic Acetylcholine Receptors. SLAS Discov 22: 155-165.
Examples:

TC#NameOrganismal TypeExample
8.A.179.1.1

Nicotinic Acetylcholine Receptor Regulator (NACHO; TMEM35A) of 167 aas and 4 TMSs in a 1 + 3 TMS arrangement (Loring 2022). It is a molecular chaperone that mediates the proper assembly and functional expression of nicotinic acetylcholine receptors (nAChRs) throughout the brain (Gu et al. 2016, Rex et al. 2017, Kweon et al. 2020). Inhibition of AMPA receptors (AMPARs, e.g., TC# 1.A.10.1.1) containing transmembrane AMPAR regulatory protein gamma-8 (TC# 8.A.61.1.10) with JNJ-55511118 (TC#8.A.179.1.1; NACHO) shows preclinical efficacy in reducing chronic repetitive alcohol self-administration (Hoffman et al. 2021). See the family description for more details. TMEM35A mediates the transmembrane transport of Epicatechin (EC), and the interaction between TMEM35A and TMPO inhibits the MAPK and NF-kappaB pathways (Ma et al. 2021).

 

NACHO or TMEM35A of Homo sapiens

 
8.A.179.1.2

Transmembrane protein 35B-like isoform X2 of 139 aas and 4 TMSs in a 1 + 3 TMS arrangement.

TMEM35B-like protein of Scyliorhinus canicula (smaller spotted catshark)

 
8.A.179.1.3

Uncharacterized protein of 133 aas and 4 TMSs in a 1 + 3 TMS arrangement.

UP of Patiria miniata (bat star)

 
8.A.179.1.4

Uncharacterized protein of 141 aas and 4 TMSs in a 1 + 3 TMS arrangement.

UP of Amphimedon queenslandica

 
8.A.179.1.5

Uncharacterized protein of 149 aas and 4 TMSs in a 1 + 3 TMS arrangement.

UP of Adineta ricciae

 
8.A.179.1.7

Uncharacterized protein of 132 aas and 4 TMSs in a 1 + 3 TMS arrangement.

UP of Diaphorina citri (Asian citrus psyllid)