Ohnishi Yoko H, Ohnishi Yoshinori N, Nakamura Takanori, Ohno Mizuki, Kennedy Pamela J, Ohkawa Yasuyuki, Nishi Akinori, Neve Rachael, Tsuzuki Teruhisa, Nestler Eric J
Fishberg Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America; Department of Pharmacology, Kurume University School of Medicine, Kurume, Fukuoka, Japan; Department of Medical Biophysics and Radiation Biology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.
Fishberg Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America; Department of Pharmacology, Kurume University School of Medicine, Kurume, Fukuoka, Japan.
PLoS One. 2015 May 11;10(5):e0126710. doi: 10.1371/journal.pone.0126710. eCollection 2015.
ΔFosB is a stable transcription factor which accumulates in the nucleus accumbens (NAc), a key part of the brain's reward circuitry, in response to chronic exposure to cocaine or other drugs of abuse. While ΔFosB is known to heterodimerize with a Jun family member to form an active transcription factor complex, there has not to date been an open-ended exploration of other possible binding partners for ΔFosB in the brain. Here, by use of yeast two-hybrid assays, we identify PSMC5-also known as SUG1, an ATPase-containing subunit of the 19S proteasomal complex-as a novel interacting protein with ΔFosB. We verify such interactions between endogenous ΔFosB and PSMC5 in the NAc and demonstrate that both proteins also form complexes with other chromatin regulatory proteins associated with gene activation. We go on to show that chronic cocaine increases nuclear, but not cytoplasmic, levels of PSMC5 in the NAc and that overexpression of PSMC5 in this brain region promotes the locomotor responses to cocaine. Together, these findings describe a novel mechanism that contributes to the actions of ΔFosB and, for the first time, implicates PSMC5 in cocaine-induced molecular and behavioral plasticity.
ΔFosB是一种稳定的转录因子，在长期接触可卡因或其他滥用药物时，会在伏隔核（NAc）中积累，伏隔核是大脑奖赏回路的关键部分。虽然已知ΔFosB会与Jun家族成员异源二聚化以形成活性转录因子复合物，但迄今为止，尚未对ΔFosB在大脑中其他可能的结合伴侣进行无限制的探索。在这里，通过酵母双杂交试验，我们鉴定出PSMC5（也称为SUG1，是19S蛋白酶体复合物中含ATP酶的亚基）是与ΔFosB相互作用的新蛋白。我们验证了内源性ΔFosB与NAc中PSMC5之间的这种相互作用，并证明这两种蛋白还与其他与基因激活相关的染色质调节蛋白形成复合物。我们进一步表明，长期使用可卡因会增加NAc中PSMC5的核水平，但不会增加其细胞质水平，并且在该脑区中过表达PSMC5会促进对可卡因的运动反应。这些发现共同描述了一种有助于ΔFosB作用的新机制，并且首次表明PSMC5参与了可卡因诱导的分子和行为可塑性。
