TY - JOUR
T1 - Regulators of the proteasome pathway, Uch37 and Rpn13, play distinct roles in mouse development
AU - Al-Shami, Amin
AU - Jhaver, Kanchan G.
AU - Vogel, Peter
AU - Wilkins, Carrie
AU - Humphries, Juliane
AU - Davis, John J.
AU - Xu, Nianhua
AU - Potter, David G.
AU - Gerhardt, Brenda
AU - Mullinax, Robert
AU - Shirley, Cynthia R.
AU - Anderson, Stephen J.
AU - Oravecz, Tamas
PY - 2010
Y1 - 2010
N2 - Rpn13 is a novel mammalian proteasomal receptor that has recently been identified as an amplification target in ovarian cancer. It can interact with ubiquitin and activate the deubiquitinating enzyme Uch37 at the 26S proteasome. Since neither Rpn13 nor Uch37 is an integral proteasomal subunit, we explored whether either protein is essential for mammalian development and survival. Deletion of Uch37 resulted in prenatal lethality in mice associated with severe defect in embryonic brain development. In contrast, the majority of Rpn13-deficient mice survived to adulthood, although they were smaller at birth and fewer in number than wild-type littermates. Absence of Rpn13 produced tissue-specific effects on proteasomal function: increased proteasome activity in adrenal gland and lymphoid organs, and decreased activity in testes and brain. Adult Rpn13-/- mice reached normal body weight but had increased body fat content and were infertile due to defective gametogenesis. Additionally, Rpn13-/- mice showed increased T-cell numbers, resembling growth hormonemediated effects. Indeed, serum growth hormone and follicular stimulating hormone levels were significantly increased in Rpn13-/- mice, while growth hormone receptor expression was reduced in the testes. In conclusion, this is the first report characterizing the physiological roles of Uch37 and Rpn13 in murine development and implicating a non-ATPase proteasomal protein, Rpn13, in the process of gametogenesis.
AB - Rpn13 is a novel mammalian proteasomal receptor that has recently been identified as an amplification target in ovarian cancer. It can interact with ubiquitin and activate the deubiquitinating enzyme Uch37 at the 26S proteasome. Since neither Rpn13 nor Uch37 is an integral proteasomal subunit, we explored whether either protein is essential for mammalian development and survival. Deletion of Uch37 resulted in prenatal lethality in mice associated with severe defect in embryonic brain development. In contrast, the majority of Rpn13-deficient mice survived to adulthood, although they were smaller at birth and fewer in number than wild-type littermates. Absence of Rpn13 produced tissue-specific effects on proteasomal function: increased proteasome activity in adrenal gland and lymphoid organs, and decreased activity in testes and brain. Adult Rpn13-/- mice reached normal body weight but had increased body fat content and were infertile due to defective gametogenesis. Additionally, Rpn13-/- mice showed increased T-cell numbers, resembling growth hormonemediated effects. Indeed, serum growth hormone and follicular stimulating hormone levels were significantly increased in Rpn13-/- mice, while growth hormone receptor expression was reduced in the testes. In conclusion, this is the first report characterizing the physiological roles of Uch37 and Rpn13 in murine development and implicating a non-ATPase proteasomal protein, Rpn13, in the process of gametogenesis.
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U2 - 10.1371/journal.pone.0013654
DO - 10.1371/journal.pone.0013654
M3 - Article
C2 - 21048919
AN - SCOPUS:78149423680
SN - 1932-6203
VL - 5
JO - PloS one
JF - PloS one
IS - 10
M1 - e13654
ER -