8.A.208. The Lysosomal Enzyme Trafficking Factor (LYSET) Family LYSET (TMEM251) family proteins include enzyme trafficking and nutrient usage of extracellular proteins (Pechincha et al. 2022). The human disease gene LYSET is essential for lysosomal enzyme transport and viral infection (Richards et al. 2022). Mammalian cells can generate amino acids through macropinocytosis and lysosomal breakdown of extracellular proteins. It is required for mannose-6-phosphate-dependent trafficking of lysosomal enzymes (Pechincha et al. 2022; Zhang et al. 2022. LYSET bridges GlcNAc-1-phosphate transferase (GNPTAB), to the membrane-bound transcription factor site-1 protease (MBTPS1), thus allowing proteolytic activation of the GNPTAB. GNPTAB is involved in the regulation of M6P-dependent Golgi-to-lysosome trafficking of lysosomal enzymes (Zhang et al. 2022). LYSET is thus an essential factor for maturation and delivery of lysosomal hydrolases (Pechincha et al. 2022). For example, LYSET is required for correct functioning of the M6P trafficking machinery and mutations in LYSET can explain the phenotype of the associated disorder (Richards et al. 2022).
References:
Pechincha, C., S. Groessl, R. Kalis, M. de Almeida, A. Zanotti, M. Wittmann, M. Schneider, R.P. de Campos, S. Rieser, M. Brandstetter, A. Schleiffer, K. Müller-Decker, D. Helm, S. Jabs, D. Haselbach, M.K. Lemberg, J. Zuber, and W. Palm. (2022). Lysosomal enzyme trafficking factor LYSET enables nutritional usage of extracellular proteins. Science 378: eabn5637.
Ramezani, M., J. Bauman, A. Singh, E. Weisbart, J. Yong, M. Lozada, G.P. Way, S.L. Kavari, C. Diaz, M. Haghighi, T.M. Batista, J. Pérez-Schindler, M. Claussnitzer, S. Singh, B.A. Cimini, P.C. Blainey, A.E. Carpenter, C.H. Jan, and J.T. Neal. (2023). A genome-wide atlas of human cell morphology. bioRxiv.
Richards, C.M., S. Jabs, W. Qiao, L.D. Varanese, M. Schweizer, P.R. Mosen, N.M. Riley, M. Klüssendorf, J.R. Zengel, R.A. Flynn, A. Rustagi, J.C. Widen, C.E. Peters, Y.S. Ooi, X. Xie, P.Y. Shi, R. Bartenschlager, A.S. Puschnik, M. Bogyo, C.R. Bertozzi, C.A. Blish, D. Winter, C.M. Nagamine, T. Braulke, and J.E. Carette. (2022). The human disease gene LYSET is essential for lysosomal enzyme transport and viral infection. Science 378: eabn5648.
Yin, Y., F. Zhang, S. Feng, K.J. Butay, M.J. Borgnia, W. Im, and S.Y. Lee. (2022). Activation mechanism of the mouse cold-sensing TRPM8 channel by cooling agonist and PIP. Science 378: eadd1268.
Zhang, W., X. Yang, Y. Li, L. Yu, B. Zhang, J. Zhang, W.J. Cho, V. Venkatarangan, L. Chen, B.B. Burugula, S. Bui, Y. Wang, C. Duan, J.O. Kitzman, and M. Li. (2022). GCAF(TMEM251) regulates lysosome biogenesis by activating the mannose-6-phosphate pathway. Nat Commun 13: 5351.
Examples:
TC#	Name	Organismal Type	Example
8.A.208.1.1	*Lysosomal enzyme trafficking factor, LYSET, of 163 aas and 3 TMSs in a 1 + 2 TMS arrangement (Richards et al.* 2022). See family description for details.**		LYSET of Homo sapiens

8.A.208.1.2	Transmembrane protein 251 or LYSET, of 136 aas and 2 or 3 TMSs in a 1 or 2 + 1 TMS arrangement.		*LYSET of Chionoecetes opilio* (snow crab)**

8.A.208.1.3	Transmembrane protein 251 of 120 aas and 2 TMSs, N- and C-terminal.		*TMP251 of Trichoplax* sp. H2**

8.A.208.1.4	Uncharacterized protein of 116 aas and 2 TMSs, 1 N-terminal and 1 C-terminal.		UP of Capsaspora owczarzaki

8.A.208.1.5	Uncharacterized protein of 107 aas with 2 TMSs		*UP of Apostichopus japonicus* (Japanese sea cucumber)**

8.A.208.1.6	Uncharacterized protein of 156 aas with 2 TMSs at residues 50 and 110.		UP of Oedothorax gibbosus

8.A.208.1.7	Uncharacterized protein of 129 aas and 3 TMSs in a 1 (N-terminal) + 2 (C-terminal) TMS arrangement.		UP of Lamellibrachia satsuma

8.A.208.1.8	Transmembrane protein 251-like protein, TMEM251/Lyset of 160 aas with 2 TMSs, 1 at the N-terminus and 1 at residue 95. It is a Golgi-resident protein essential for mannose-6-phosphate-dependent trafficking of lysosomal enzymes (Ramezani et al. 2023).		TMEM251-like protein of Pecten maximus

8.A.208.1.9	Lysosomal enzyme trafficking factor isoform X2 of 131 aas and 3 TMSs in a 1 (N-terminal) + 2 (C-terminal) TMS arrangement.		Trafficing Factor of Stegostoma tigrinum