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Published online
doi:10.1083/jcb.200611036
The Journal of Cell Biology, Vol. 177, No. 1, 51-61
The Rockefeller University Press, 0021-9525 $30.00
© Tuvia et al.
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Article

The ubiquitin E3 ligase POSH regulates calcium homeostasis through spatial control of Herp



Shmuel Tuvia, Daniel Taglicht, Omri Erez, Iris Alroy, Iris Alchanati, Vivian Bicoviski, Mally Dori-Bachash, Danny Ben-Avraham, and Yuval Reiss

Proteologics Ltd., Kiryat Weizmann, Rehovot 76124, Israel

Correspondence to Yuval Reiss: yuval{at}proteologics.com

The ubiquitin (Ub) domain protein Herp plays a crucial role in the maintenance of calcium homeostasis during endoplasmic reticulum (ER) stress. We now show that Herp is a substrate as well as an activator of the E3 Ub ligase POSH. Herp-mediated POSH activation requires the Ubl domain and exclusively promotes lysine-63–linked polyubiquitination. Confocal microscopy demonstrates that Herp resides mostly in the trans-Golgi network, but, shortly after calcium perturbation by thapsigargin (Tpg), it appears mainly in the ER. Substitution of all lysine residues within the Ubl domain abolishes lysine-63–linked polyubiquitination of Herp in vitro and calcium-induced Herp relocalization that is also abrogated by the overexpression of a dominant-negative POSHV14A. A correlation exists between the kinetics of Tpg-induced Herp relocalization and POSH-dependent polyubiquitination. Finally, the overexpression of POSH attenuates, whereas the inhibition of POSH by the expression of POSHV14A or by RNA interference enhances Tpg-induced calcium burst. Altogether, these results establish a critical role for POSH-mediated ubiquitination in the maintenance of calcium homeostasis through the spatial control of Herp.

S. Tuvia's present address is Bioline Innovations Jerusalem, Jerusalem 91450, Israel.

I. Alroy's present address is Pharmos Ltd., Kiryat Weizmann, Rehovot 76326, Israel.

M. Dori-Bachash's present address is Dept. of Plant Pathology and Microbiology, Faculty of Agricultural, Food, and Environmental Quality Sciences, Hebrew University of Jerusalem, Rehovot 76100, Israel.

Abbreviations used in this paper: AMFR, autocrine motility factor receptor; CHX, cycloheximide; ERAD, ER-associated degradation; MBP, maltose-binding protein; NRIF, neurotrophin receptor–interacting factor; shRNA, small hairpin RNA; tHerp, truncated Herp; Tm, tunicamycin; Tpg, thapsigargin; TRAF, TNF receptor–associated factor; Ub, ubiquitin.


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