8.A.122. The Vesicular Membrane Neurensin/TMEM74 (Neurensin/TMEM74) Family
Nuerensins may play important roles in neural organelle transport, transduction of nerve signals and nerve growth, and may also play a role in neurite extension. The homologous transmembrane protein 74 (TMEM74), which contains two putative transmembrane domains and exhibits high levels of mRNA in the brain, is closely associated with the pathogenesis of anxiety disorders (Shao et al. 2019). TMEM74 is decreased in the serum of patients with anxiety and the basolateral amygdaloid nucleus (BLA) in chronic stress mice. Genetic deletion of Tmem74 or selective knockdown of Tmem74 in BLA pyramidal neurons resulted in anxiety-like behaviors in mice. Whole-cell recordings in BLA pyramidal neurons revealed lower hyperpolarization-activated cation current (Ih) and greater input resistance and excitability in Tmem74(-/-) neurons than in wild-type neurons. Accordingly, surface expression of hyperpolarization-activated cyclic nucleotide-gated 1 (HCN1) channels was also lower in the BLA of Tmem74(-/-) mice. The Ih current blocker ZD7288 mimicked these effects in BLA pyramidal neurons in wild-type mice but not in Tmem74(-/-) mice. Consistent with the improvement in anxiety-like behaviors, Tmem74 overexpression restored HCN1 channel trafficking and pyramidal neuron excitability in the BLA of Tmem74(-/-) and chronic stress mice. Interactions between Tmem74 and HCN1 are physiologically relevant, and TMS1 is essential for the cellular membrane localization of Tmem74 to enhance Ih. Thus, Tmem74 coupling with HCN1 acts as a critical component in the pathophysiology of anxiety and is a potential target for new treatments of anxiety disorders (Shao et al. 2019).
References:
Neurensin-1, NRSN1, Neuro-p24, vesicular membrane protein of 24kDa, VMP-p24 of 195 aas and 2 TMSs. May play a role in neural organelle transport, and in transduction of nerve signals or in nerve growth. May also play a role in neurite extension (Nagata et al. 2006).
Animals
Neuensin-1 of Homo sapiens
Neurensin-2 (NRSN2) of 204 aas and 2 TMSs. Both Neurensin-1, and -2 are localized to small vesicles in neural cells (Nakanishi et al. 2006). NRSN2 promotes lung and ovarian cancer as well as osteosarcoma cell proliferation and growth (Zhang et al. 2015; Keremu et al. 2017; Tang et al. 2017).
Animals
Neurensin-2 of Homo sapiens
Neurensin-1 of 195 aas and 2 TMSs.
Neurensin-1 of Jaculus jaculus (lesser Egyptian jerboa)
TMEM74 (ATG16L1) of 305 aas and 2 TMSs. An autosomal lysosomal protein that regulates autophagy (Yu et al. 2008). A coding polymorphism of human ATG16L1 (T300A) increases the risk of Crohn's disease and enhance susceptibility of ATG16L1 to caspase cleavage, and the ATG16L1 WD domain and linker regulate lipid trafficking to maintain plasma membrane integrityand to limit influenza virus infection (Bone et al. 2025). T300A also alters the ability of the C-terminal WD40-repeat domain of ATG16L1 to interact with an amino acid motif that recognizes this region. Such an alteration impairs the unconventional autophagic activity of TMEM59, a transmembrane protein that contains the WD40 domain-binding motif, and disrupts its normal intracellular trafficking and its ability to engage ATG16L1 in response to bacterial infection. TMEM59-induced autophagy is blunted in cells expressing the fragments generated by caspase processing of the ATG16L1-T300A risk allele, whereas canonical autophagy remains unaffected. Thus, the T300A polymorphism alters the function of motif-containing molecules that engage ATG16L1 through the WD40 domain, either by influencing this interaction under non-stressful conditions or by inhibiting their downstream autophagic signalling after caspase-mediated cleavage (Boada-Romero et al. 2016). Tethering ATG16L1 or LC3 induces targeted autophagic degradation of protein aggregates and mitochondria (Mei et al. 2023). The mammalian protein ATG16L1, primarily appreciated for its role in canonical autophagy and in noncanonical membrane atg8ylation processes, controls V-ATPase. An ATG16L1 knockout elevated V-ATPase activity, increased the V1 presence on endomembranes, and increased the number of acidified intracellular compartments (Duque et al. 2025).
TMEM74 of Homo sapiens
Transmembrane protein 74B, TMEM74B of 160 aas and 2 TMSs.
TMEM74B of Haliaeetus leucocephalus (Bald eagle)
Uncharacterized protein of 144 aas and 2 TMSs.
UP of Crassostrea virginica (eastern oyster)