Mutations in the ubiquitin-binding domain of OPTN/optineurin interfere with autophagy-mediated degradation of misfolded proteins by a dominant-negative mechanism

Shen, Wen-Chuan; Li, Huei-Ying; Chen, Guang-Chao; Chern, Yijuang; Tu, Pang‐Hsien

doi:10.4161/auto.36098

Cited by 142 publications

(109 citation statements)

References 53 publications

(80 reference statements)

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“…Previous work has suggested a direct interaction mediated by the RRL motif in myosin VI and the UBDs of optineurin (Sahlender et al, 2005; Shen et al, 2015). Our results suggest that ubiquitin may be part of the myosin VI interaction with this adaptor protein.…”

Section: Resultsmentioning

confidence: 99%

Myosin VI Contains a Compact Structural Motif that Binds to Ubiquitin Chains

Wollscheid

Nowicka

et al. 2016

Cell Reports

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SUMMARY Myosin VI is critical for cargo trafficking and sorting during early endocytosis and autophagosome maturation, with abnormalities linked to cancers, neurodegeneration, deafness, and hypertropic cardiomyopathy. Herein, we identify a structured domain in myosin VI, MyUb (Myosin VI Ubiquitin-binding domain), that binds to ubiquitin chains, especially those linked via K63, K11, and K29. We solve the solution structure of MyUb, and of MyUb:K63-linked diubiquitin. MyUb folds as a compact, helix-turn-helix-like motif and nestles between the ubiquitins of K63-linked diubiquitin, interacting with distinct surfaces of each. A nine amino acid extension at the C-terminal helix (Helix2) of MyUb is required for myosin VI interaction with endocytic and autophagic adaptors. Structure-guided mutations revealed that a functional MyUb is necessary for optineurin interaction. In addition, we found that an isoform-specific helix restricts MyUb binding to ubiquitin chains. This work provides fundamental insights into myosin VI interaction with ubiquitinated cargo and functional adaptors.

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Section: Resultsmentioning

confidence: 99%

Myosin VI Contains a Compact Structural Motif that Binds to Ubiquitin Chains

Wollscheid

Nowicka

et al. 2016

Cell Reports

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“…Recent studies of the effects of OPTN mutations have suggested a dominant‐negative or gain‐of‐function effect for many of the characterized disease‐associated variants (Shen et al. 2014; Turturro et al. 2014).…”

Section: Discussionmentioning

confidence: 99%

Identification of an Alu‐repeat‐mediated deletion of OPTN upstream region in a patient with a complex ocular phenotype

Schilter

Reis

Сорокина

et al. 2015

Molec Gen & Gen Med

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Genetic causes of ocular conditions remain largely unknown. To reveal the molecular basis for a congenital ocular phenotype associated with glaucoma we performed whole‐exome sequencing (WES) and whole‐genome copy number analyses of patient DNA. WES did not identify a causative variant. Copy number variation analysis identified a deletion of 10p13 in the patient and his unaffected father; the deletion breakpoint contained a single 37‐bp sequence that is normally present in two distinct Alu repeats separated by ~181 kb. The deletion removed part of the upstream region of optineurin (OPTN) as well as the upstream sequence and two coding exons of coiled‐coil domain containing 3 (CCDC3); analysis of the patient's second allele showed normal OPTN and CCDC3 sequences. Studies of zebrafish orthologs identified expression in the developing eye for both genes. OPTN is a known factor in dominant adult‐onset glaucoma and Amyotrophic Lateral Sclerosis (ALS). The deletion eliminates 98 kb of the OPTN upstream sequence leaving only ~1 kb of the proximal promoter region. Comparison of transcriptional activation capability of the 3 kb normal and the rearranged del(10)(p13) OPTN promoter sequences demonstrated a statistically significant decrease for the deleted allele; sequence analysis of the entire deleted region identified multiple conserved elements with possible cis‐regulatory activity. Additional screening of CCDC3 indicated that heterozygous loss‐of‐function alleles are unlikely to cause congenital ocular disease. In summary, we report the first regulatory region deletion involving OPTN, caused by Alu‐mediated nonallelic homologous recombination and possibly contributing to the patient's ocular phenotype. In addition, our data indicate that Alu‐mediated rearrangements of the OPTN upstream region may represent a new source of affected alleles in human conditions. Evaluation of the upstream OPTN sequences in additional ocular and ALS patients may help to determine the role of this region, if any, in human disease.

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“…With the discovery of p62 as a selective autophagy receptor, it became clear that selective autophagy of protein aggregates may play an important role in neurodegenerative diseases[83]. Given the importance of this degradation pathway, it is not surprising that there is a significant amount of redundancy with multiple selective autophagy receptors also mediating aggrephagy including NBR1 and OPTN[54,71]. …”

Section: P62: Multi-functional Selective Autophagy Receptor With Rolementioning

confidence: 99%

Mechanisms of Selective Autophagy in Normal Physiology and Cancer

Mancias

Kimmelman

2016

Journal of Molecular Biology

163

123

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Selective autophagy is critical for regulating cellular homeostasis by mediating lysosomal turnover of a wide variety of substrates including proteins, aggregates, organelles, and pathogens via a growing class of molecules termed selective autophagy receptors. The molecular mechanisms of selective autophagy receptor action and regulation are complex. Selective autophagy receptors link their bound cargo to the autophagosomal membrane by interacting with lipidated ATG8 proteins (LC3/GABARAP) that are intimately associated with the autophagosome membrane. The cargo signals that selective autophagy receptors recognize are diverse but their recognition can be broadly grouped into two classes, ubiquitin-dependent cargo recognition versus ubiquitin-independent. The roles of post-translational modification of selective autophagy receptors in regulating these pathways in response to stimuli are an active area of research. Here we will review recent advances in the identification of selective autophagy receptors and their regulatory mechanisms. Given its importance in maintaining cellular homeostasis, disruption of autophagy can lead to disease including neurodegeneration and cancer. The role of autophagy in cancer is complex as autophagy can mediate promotion or inhibition of tumorigenesis. Here we will also review the importance of autophagy in cancer with a specific focus on the role of selective autophagy receptors.

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Mutations in the ubiquitin-binding domain of OPTN/optineurin interfere with autophagy-mediated degradation of misfolded proteins by a dominant-negative mechanism

Cited by 142 publications

References 53 publications

Myosin VI Contains a Compact Structural Motif that Binds to Ubiquitin Chains

Myosin VI Contains a Compact Structural Motif that Binds to Ubiquitin Chains

Identification of an Alu‐repeat‐mediated deletion of OPTN upstream region in a patient with a complex ocular phenotype

Mechanisms of Selective Autophagy in Normal Physiology and Cancer

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