Figure 8

A working model for the regulation of SPL7 function. Cu supply depends on extracellular input and mobilization from intracellular stores via selective Cu-transport proteins, COPT. Acquired Cu is complexed by a set of metallochaperones, like CCH and ATX1, and delivered to specific targets. As main orchestrator of the Cu starvation response, SPL7 may be among these targets in order to become or remain repressed in the presence of sufficient Cu. This may be achieved through a direct interaction with delivered Cu resulting in an inability of SPL7 to bind to CuRE motifs in the promoter regions of its targets genes (1). In addition or alternatively, proteolytic processing of ER membrane-tethered SPL7 may be repressed in the presence of Cu (2). As a consequence, activation of SPL7 in response to Cu-deficiency may thus result from a relief of these repression mechanisms. Furthermore, ER stress caused by a failure to fulfil the demand for Cu of proteins involved in the secretory pathway, may actively promote the release of the membrane-bound SPL7 (3). Finally, a precocious dimerization to modulate the Cu deficiency response as the amount of released SPL7 continues to raise may prevent SPL7 from entering the nucleus either due to NLS masking or exceeding the size exclusion limit of the nuclear pore (4).