MACO1

MACO1 (macoilin/TMEM57) encodes a conserved multi-transmembrane protein of the rough endoplasmic reticulum that is expressed broadly and specifically in the nervous system, where it controls neuronal excitability and sensory signaling (PMID:21437263, PMID:21589894). In C. elegans, loss of maco-1 produces presynaptic neurotransmission defects (aldicarb resistance, levamisole sensitivity) and abolishes the rising-O2 Ca2+ response of the PQR sensory neuron in a manner mirroring mutation of the L-type voltage-gated Ca2+ channel α1 subunit egl-19, supporting a model in which macoilin acts within the ER to regulate the assembly or trafficking of ion channels or their regulators (PMID:21437263). ER localization and a neuronal function are conserved: human MACO1 localizes to the rough ER and weakly rescues the thermotaxis defect of maco-1 mutants, which themselves show altered thermosensory Ca2+ responses in AFD and AIY neurons (PMID:21589894). Through this control of sensory Ca2+ dynamics, MACO-1 acts downstream of the TIR-1/JNK-1 pathway to promote recovery of attenuated odor-evoked responses, thereby driving forgetting of olfactory adaptation, and is also required for pheromone-induced dauer formation (PMID:28924007, PMID:26976437). Independently, maco-1 is the molecular endpoint of a trans-kingdom small-RNA silencing mechanism: small RNAs from Pseudomonas species (PA14-derived P11; P. vranovensis Pv1) bear complementarity to maco-1 and downregulate it via the RNAi/piRNA pathway to drive learned, transgenerationally inherited pathogen avoidance, a circuit in which maco-1 acts downstream of or parallel to the VAB-1 receptor (PMID:32908307, PMID:38547071, PMID:40267186).

1. 2011 High

   Established macoilin as a neuron-specific rough-ER protein whose loss disrupts presynaptic function and sensory Ca2+ responses, generating the model that it regulates ion channel assembly/trafficking from the ER.

   Evidence Fluorescent localization, in vivo Ca2+ imaging of PQR, aldicarb/levamisole pharmacology, and genetic epistasis with egl-19/nca-1/nca-2 in C. elegans

   PMID:21437263

   Open questions at the time

   • No direct biochemical demonstration that macoilin binds or chaperones EGL-19 or other channels
   • Mechanism distinguishing assembly versus trafficking not resolved
2. 2011 High

   Demonstrated cross-species conservation of ER localization and neuronal function, showing human MACO1 can substitute for the worm protein in thermotaxis.

   Evidence Subcellular localization, cross-species rescue by human MACO1 expression, and Ca2+ imaging of AFD/AIY neurons

   PMID:21589894

   Open questions at the time

   • Rescue was only weak/partial
   • Human MACO1 molecular activity not directly assayed in a mammalian system
3. 2016 Medium

   Placed MACO-1 in pheromone signaling by showing it is required for ascaroside-pheromone-induced dauer formation.

   Evidence Forward EMS genetic screen and dauer formation assays in C. elegans

   PMID:26976437

   Open questions at the time

   • No molecular mechanism linking MACO-1 to pheromone detection/integration
   • Site of action within the dauer pathway undefined
4. 2017 High

   Connected MACO-1 to a defined signaling pathway by showing it acts downstream of TIR-1/JNK-1 to promote recovery of sensory Ca2+ responses and forgetting of olfactory adaptation.

   Evidence Forward suppressor screen, double-mutant epistasis, in vivo Ca2+ imaging, and histamine-gated chloride channel neuronal silencing

   PMID:28924007

   Open questions at the time

   • How ER-localized MACO-1 mechanistically restores Ca2+ response recovery is unknown
   • Relationship between this role and channel trafficking not established
5. 2020 High

   Identified maco-1 as the silencing target of a bacterial non-coding small RNA, defining it as the genetic endpoint of a trans-kingdom RNAi/piRNA pathway driving heritable pathogen avoidance.

   Evidence PA14 sRNA purification and feeding, RNAi knockdown, loss-of-function genetics, and behavioral/transgenerational assays with RNAi/piRNA pathway epistasis

   PMID:32908307

   Open questions at the time

   • How reduced MACO-1 in specific neurons translates to avoidance behavior not mechanistically resolved
   • Link between ER/channel function and avoidance circuit not established
6. 2024 High

   Generalized the sRNA-targeting mechanism by showing a distinct Pseudomonas species uses an independent small RNA (Pv1) complementary to maco-1 to induce heritable avoidance.

   Evidence Bacterial sRNA sequencing, sRNA deletion/rescue for necessity and sufficiency, and transgenerational avoidance assays

   PMID:38547071

   Open questions at the time

   • Whether other pathogens converge on maco-1 broadly unknown
   • Downstream consequences of maco-1 downregulation on neuronal physiology not measured
7. 2025 Medium

   Positioned MACO-1 relative to the VAB-1 receptor within the avoidance circuit, showing VAB-1 loss reduces maco-1 expression and combined knockdown induces avoidance.

   Evidence RNAi knockdown, genetic epistasis, expression analysis, and behavioral avoidance assays

   PMID:40267186

   Open questions at the time

   • Placement inferred from expression-level changes, not direct biochemical interaction
   • Whether VAB-1 regulates maco-1 directly or indirectly unknown

• The biochemical activity of macoilin at the ER — its direct binding partners, the channels it assembles or traffics, and the molecular basis of its conserved neuronal function in mammals — remains undefined.
• No identified direct physical substrate or interactor
• No structural or domain-level mechanism
• Mammalian (human MACO1) cellular function not characterized beyond ER localization