Compositional complexity of rods and rings

Mol Biol Cell. 2018 Sep 15;29(19):2303-2316. doi: 10.1091/mbc.E18-05-0274. Epub 2018 Jul 19.

Abstract

Rods and rings (RRs) are large linear- or circular-shaped structures typically described as polymers of IMPDH (inosine monophosphate dehydrogenase). They have been observed across a wide variety of cell types and species and can be induced to form by inhibitors of IMPDH. RRs are thought to play a role in the regulation of de novo guanine nucleotide synthesis; however, the function and regulation of RRs is poorly understood. Here we show that the regulatory GTPase, ARL2, a subset of its binding partners, and several resident proteins at the endoplasmic reticulum (ER) also localize to RRs. We also have identified two new inducers of RR formation: AICAR and glucose deprivation. We demonstrate that RRs can be disassembled if guanine nucleotides can be generated by salvage synthesis regardless of the inducer. Finally, we show that there is an ordered addition of components as RRs mature, with IMPDH first forming aggregates, followed by ARL2, and only later calnexin, a marker of the ER. These findings suggest that RRs are considerably more complex than previously thought and that the function(s) of RRs may include involvement of a regulatory GTPase, its effectors, and potentially contacts with intracellular membranes.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminoimidazole Carboxamide / analogs & derivatives
  • Aminoimidazole Carboxamide / pharmacology
  • Animals
  • Carbon-Nitrogen Ligases / metabolism
  • Cell Line
  • Endoplasmic Reticulum / drug effects
  • Endoplasmic Reticulum / metabolism
  • Endoplasmic Reticulum / ultrastructure
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Fibroblasts / pathology
  • Fibroblasts / ultrastructure
  • GTP-Binding Proteins / metabolism
  • Glucose / deficiency
  • Guanosine / pharmacology
  • Humans
  • IMP Dehydrogenase / chemistry*
  • Intracellular Membranes / drug effects
  • Intracellular Membranes / metabolism
  • Kinetics
  • Lesch-Nyhan Syndrome / pathology
  • Mice
  • Mycophenolic Acid / pharmacology
  • Protein Transport
  • Ribonucleotides / pharmacology

Substances

  • Ribonucleotides
  • Guanosine
  • Aminoimidazole Carboxamide
  • IMP Dehydrogenase
  • ARL2 protein, human
  • GTP-Binding Proteins
  • Carbon-Nitrogen Ligases
  • CTP synthetase
  • AICA ribonucleotide
  • Mycophenolic Acid
  • Glucose