Tripartite Motif-Containing Protein 32 (TRIM32): What Does It Do for Skeletal Muscle?

Jeong, Seung Yeon; Choi, Jun Hee; Kim, Jooho; Woo, Jin Seok; Lee, Eun Hui

doi:10.3390/cells12162104

Cited by 3 publications

References 168 publications

(441 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

Optogenetic induction of mechanical muscle stress identifies myosin regulatory ubiquitin ligase NHL-1 in C. elegans

Kutzner,

Bauer,

Lackmann

et al. 2024

Nat Commun

View full text Add to dashboard Cite

Mechanical stress during muscle contraction is a constant threat to proteome integrity. However, there is a lack of experimental systems to identify critical proteostasis regulators under mechanical stress conditions. Here, we present the transgenic Caenorhabditis elegans model OptIMMuS (Optogenetic Induction of Mechanical Muscle Stress) to study changes in the proteostasis network associated with mechanical forces. Repeated blue light exposure of a muscle-expressed Chlamydomonas rheinhardii channelrhodopsin-2 variant results in sustained muscle contraction and mechanical stress. Using OptIMMuS, combined with proximity labeling and mass spectrometry, we identify regulators that cooperate with the myosin-directed chaperone UNC-45 in muscle proteostasis. One of these is the TRIM E3 ligase NHL-1, which interacts with UNC-45 and muscle myosin in genetic epistasis and co-immunoprecipitation experiments. We provide evidence that the ubiquitylation activity of NHL-1 regulates myosin levels and functionality under mechanical stress. In the future, OptIMMuS will help to identify muscle-specific proteostasis regulators of therapeutic relevance.

show abstract

Optogenetic induction of mechanical muscle stress identifies myosin regulatory ubiquitin ligase NHL-1 in C. elegans

Kutzner,

Bauer,

Lackmann

et al. 2024

Nat Commun

View full text Add to dashboard Cite

show abstract

A homozygousATP2A2variant alters sarcoendoplasmic reticulum Ca²⁺-ATPase 2 function in skeletal muscle and causes a novel vacuolar myopathy

Llansó,

Ravenscroft,

Aceituno

et al. 2024

Preprint

View full text Add to dashboard Cite

Background: Sarcoendoplasmic reticulum Ca2+-ATPase isoform 2 (SERCA2), encoded by ATP2A2, is a key protein involved in intracellular Ca2+ homeostasis. The transcript SERCA2a is predominantly expressed in cardiac muscle and in type I myofibers, while SERCA2b is ubiquitously expressed including in skin cells. To date, variants in this gene were reported to be the cause of Darier disease, an autosomal dominant dermatologic disorder, but have never been linked to primary skeletal muscle disease. We describe four patients suffering from a novel hereditary myopathy caused by a homozygous missense variant in ATP2A2. Methods: We studied a family with four affected individuals suffering from an adult-onset progressive skeletal myopathy. We performed a comprehensive evaluation of the clinical phenotype, serum CK levels, muscle MRI, and muscle biopsy, with genetic workup by means of gene panel sequencing followed by whole genome sequencing and segregation analysis. Immunohistochemistry and western blot (WB) to evaluate SERCA2 and SERCA1 expression in skeletal muscle was performed. We evaluated kinetics of Ca2+ handling following caffeine exposure or voltage-induced sarcolemma depolarization in patient myoblasts and myotubes, compared to healthy controls. Results: Four siblings in their fifties developed in early adulthood symmetric proximal weakness in lower limbs, which was slowly progressive over time. They had no skin or cardiac involvement. Biopsy findings in two affected individuals showed small vacuoles restricted to type I myofibers. Ultrastructural analysis showed dilation and proliferation of T-tubules, swelling of sarcoplasmic reticulum and autophagic vacuoles. Genome sequencing revealed a homozygous variant in ATP2A2 (c.1117G>A, p.(Glu373Lys)) which segregated with the disease. Immunohistochemistry suggested SERCA2 mislocalization in patient myofibers compared to controls. WB did not show changes in the amount or molecular weight of the protein. In vitro functional studies revealed delayed sarcoendoplasmic reticulum Ca2+ reuptake in patient myotubes, consistent with an altered pumping capacity of SERCA2 after cell stimulation with caffeine or depolarization. Conclusions: We report a novel adult-onset vacuolar myopathy caused by a homozygous variant in ATP2A2, resulting in a pure skeletal muscle phenotype with a limb-girdle distribution. Biopsy findings and functional studies demonstrating an impaired function of SERCA2 and consequent Ca2+ dysregulation in slow-twitch skeletal myofibers highly support the pathogenicity of the variant.

show abstract

Ubiquitination Insight from Spinal Muscular Atrophy—From Pathogenesis to Therapy: A Muscle Perspective

Bolado-Carrancio,

Tapia,

Rodríguez-Rey

2024

IJMS

View full text Add to dashboard Cite

Spinal muscular atrophy (SMA) is one of the most frequent causes of death in childhood. The disease’s molecular basis is deletion or mutations in the SMN1 gene, which produces reduced survival motor neuron protein (SMN) levels. As a result, there is spinal motor neuron degeneration and a large increase in muscle atrophy, in which the ubiquitin–proteasome system (UPS) plays a significant role. In humans, a paralogue of SMN1, SMN2 encodes the truncated protein SMNΔ7. Structural differences between SMN and SMNΔ7 affect the interaction of the proteins with UPS and decrease the stability of the truncated protein. SMN loss affects the general ubiquitination process by lowering the levels of UBA1, one of the main enzymes in the ubiquitination process. We discuss how SMN loss affects both SMN stability and the general ubiquitination process, and how the proteins involved in ubiquitination could be used as future targets for SMA treatment.

show abstract

Tripartite Motif-Containing Protein 32 (TRIM32): What Does It Do for Skeletal Muscle?

Cited by 3 publications

References 168 publications

Optogenetic induction of mechanical muscle stress identifies myosin regulatory ubiquitin ligase NHL-1 in C. elegans

Optogenetic induction of mechanical muscle stress identifies myosin regulatory ubiquitin ligase NHL-1 in C. elegans

A homozygousATP2A2variant alters sarcoendoplasmic reticulum Ca²⁺-ATPase 2 function in skeletal muscle and causes a novel vacuolar myopathy

Ubiquitination Insight from Spinal Muscular Atrophy—From Pathogenesis to Therapy: A Muscle Perspective

Contact Info

Product

Resources

About

Tripartite Motif-Containing Protein 32 (TRIM32): What Does It Do for Skeletal Muscle?

Cited by 3 publications

References 168 publications

Optogenetic induction of mechanical muscle stress identifies myosin regulatory ubiquitin ligase NHL-1 in C. elegans

Optogenetic induction of mechanical muscle stress identifies myosin regulatory ubiquitin ligase NHL-1 in C. elegans

A homozygousATP2A2variant alters sarcoendoplasmic reticulum Ca2+-ATPase 2 function in skeletal muscle and causes a novel vacuolar myopathy

Ubiquitination Insight from Spinal Muscular Atrophy—From Pathogenesis to Therapy: A Muscle Perspective

Contact Info

Product

Resources

About

A homozygousATP2A2variant alters sarcoendoplasmic reticulum Ca²⁺-ATPase 2 function in skeletal muscle and causes a novel vacuolar myopathy