8.A.124.  The Tetra Spanning Protein 1 (Tts1) Family 

The fission yeast Schizosaccharomyces pombe undergoes 'closed' mitosis where the nuclear envelope (NE) stays intact throughout chromosome segregation. Tts1, the fission yeast TMEM33 protein, has been implicated in organizing the peripheral endoplasmic reticulum (ER), but it also functions in remodeling the NE during mitosis (Zhang and Oliferenko 2014). Tts1 promotes insertion of spindle pole bodies (SPBs) in the NE at the onset of mitosis and modulates distribution of the nuclear pore complexes (NPCs; TC# 1.I.1)) during mitotic NE expansion. Structural features that drive partitioning of Tts1 to high-curvature ER domains are crucial for both aspects of its function. An amphipathic helix located at the C-terminus of Tts1 is important for ER shaping and modulating the mitotic NPC distribution. The evolutionarily conserved residues at the luminal interface of the third transmembrane region function specifically in promoting SPB-NE insertion (Zhang and Oliferenko 2014).

Endoplasmic reticulum (ER) stress leads to activation of the unfolded protein response signaling cascade and induction of apoptotic cell death and autophagy. Sakabe et al. 2015 showed that TMEM33, is in the ER, is ER stress-inducible and binds PERK. Overexpression correlates with increased expression of apoptotic signals including cleaved caspase-7, PARP and an autophagosome protein LC3II, and reduced expression of the autophagy marker p62. TMEM33 may function as a determinant of the ER stress-responsive events in cancer cells.

In humans and mice, mutations in the polycystins cause autosomal dominant polycystic kidney disease (ADPKD). Arhatte et al. 2019 showed that TMEM33 interacts with the ion channel polycystin-2 (PC2) at the ER membrane, enhancing its opening over the whole physiological calcium range in ER liposomes fused to planar bilayers. Consequently, TMEM33 reduces intracellular calcium content in a PC2-dependent manner, impairs lysosomal calcium refilling, causes cathepsin translocation, inhibition of autophagic flux upon ER stress, as well as sensitization to apoptosis. Invalidation of TMEM33 in the mouse exerts a potent protection against renal ER stress. By contrast, TMEM33 does not influence pkd2-dependent renal cystogenesis in the zebrafish. Thus, a key role for TMEM33 in the regulation of intracellular calcium homeostasis of renal proximal convoluted tubule cells is established as a causal link between TMEM33 and acute kidney injury (Arhatte et al. 2019).



Arhatte, M., G.S. Gunaratne, C. El Boustany, I.Y. Kuo, C. Moro, F. Duprat, M. Plaisant, H. Duval, D. Li, N. Picard, A. Couvreux, C. Duranton, I. Rubera, S. Pagnotta, S. Lacas-Gervais, B.E. Ehrlich, J.S. Marchant, A.M. Savage, F.J.M. van Eeden, R.N. Wilkinson, S. Demolombe, E. Honoré, and A. Patel. (2019). TMEM33 regulates intracellular calcium homeostasis in renal tubular epithelial cells. Nat Commun 10: 2024.

Sakabe, I., R. Hu, L. Jin, R. Clarke, and U.N. Kasid. (2015). TMEM33: a new stress-inducible endoplasmic reticulum transmembrane protein and modulator of the unfolded protein response signaling. Breast Cancer Res Treat 153: 285-297.

Urade, T., Y. Yamamoto, X. Zhang, Y. Ku, and T. Sakisaka. (2014). Identification and characterization of TMEM33 as a reticulon-binding protein. Kobe J Med Sci 60: E57-65.

Zhang, D. and S. Oliferenko. (2014). Tts1, the fission yeast homologue of the TMEM33 family, functions in NE remodeling during mitosis. Mol. Biol. Cell 25: 2970-2983.


TC#NameOrganismal TypeExample

The tetra spanning protein 1 Tts1, of the TMEM33 family; 279 aas and 4 TMSs.


Tts1 of Schizosaccharomyces pombe


Tts1 homologue of 350 aas and 3 or 4 TMSs.


TMEM33 family protein of Acanthamoeba castellanii


TMEM33 of 247 aas and 4 TMSs.  Acts as a regulator of the tubular endoplasmic reticulum (ER) network. Suppresses the RTN3/4-induced formation of the ER tubules (Urade et al. 2014). Positively regulates PERK-mediated and IRE1-mediated unfolded protein response signaling (Sakabe et al. 2015).TMEM33 in mice regulates Ca2+ fluxes by interacting with the ion channel polycystin-2 (PC2) at the ER membrane, enhancing its opening over the whole physiological calcium range (Arhatte et al. 2019).

TMEM33 of Homo sapiens