Review Volume 12, Issue 14 pp 15169—15182

Role of CPEB3 protein in learning and memory: new insights from synaptic plasticity

Figure 2. Subcellular distribution and functional states of neuronal CPEB3. CPEB3 is expressed both in nuclear and cytoplasmic fractions. In the nucleus, CPEB3 is synthesized and exported to the cytoplasm by a CRM1-mediated nuclear export signal. In the cytoplasm, CPEB3 plays a dual role in translation of target mRNA, largely influenced by the glutamatergic activation of the local synapse. In its basal state, CPEB3 is soluble, SUMOylated, and monomeric. This form of CPEB3 recruits target mRNA into P-bodies. NMDA stimulation signals transformation of CPEB3 by 1) calpain 2-mediated cleavage of CPEB3 interacting domains that promote its monomeric state or 2) Neurl1-mediated ubiquitination that promotes CPEB3 aggregation. CPEB3 aggregation promotes a functional switch into a translational activation state, generally occurring in polysomes. Finally, cytosolic CPEB3 can be translocated back into the nucleus by the importin IPO5 (Ran GDP-dependent) in a CMR1–mediated manner, where CPEB3 then interacts with Satb5 to repress transcription of Satb5-interacting mRNA.