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Mkrn3 functions as a novel ubiquitin E3 ligase to inhibit Nptx1 during puberty initiation

Huifang Liu1, Xiangxin Kong1, Fengling Chen1

  • 1Department of Endocrinology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Oncotarget
|November 22, 2017
PubMed

Insights

Makorin ring finger protein 3 (Mkrn3) loss-of-function mutations cause central precocious puberty (CPP). This study shows Mkrn3 suppresses Nptx1 activity, crucial for puberty initiation, via polyubiquitination.

Area of Science:

  • Endocrinology
  • Molecular Biology
  • Neuroscience

Background:

  • Central precocious puberty (CPP) involves premature activation of the hypothalamic-pituitary-gonadal axis.
  • Makorin ring finger protein 3 (Mkrn3) loss-of-function mutations are linked to CPP, but its function remains unclear.
  • Mkrn3's role as a putative E3 ubiquitin ligase requires functional elucidation.

Purpose of the Study:

  • To investigate the molecular function of Mkrn3 in puberty initiation.
  • To explore the interaction between Mkrn3 and Nptx1 in the hypothalamus.
  • To determine the role of Mkrn3's Ring finger domain in regulating Nptx1 activity.

Main Methods:

  • Expression analysis of Mkrn3 and Nptx1 in mouse hypothalamus during puberty initiation.
  • Co-immunoprecipitation assays to assess Mkrn3-Nptx1 interaction.
  • In vitro ubiquitination assays to evaluate Mkrn3's effect on Nptx1.

Main Results:

  • Mkrn3 expression inversely correlated with Nptx1 in the hypothalamus during puberty initiation.
  • Mkrn3 directly interacts with and suppresses Nptx1 activity.
  • Mkrn3's Ring finger domain is essential for Nptx1 polyubiquitination and subsequent regulation.

Conclusions:

  • Mkrn3 functions as a ubiquitin ligase to polyubiquitinate Nptx1, thereby inhibiting its activity.
  • This Mkrn3-Nptx1 regulatory mechanism is critical for normal puberty initiation.
  • The findings provide molecular insights into Mkrn3's role in regulating pubertal timing.
Keywords:
Mkrn3Nptx1hypothalamuspubertyubiquitination

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