The cell surface hyaluronidase TMEM2 is essential for systemic hyaluronan catabolism and turnover

Tobisawa, Yuki; Fujita, Naoki; Yamamoto, Hayato; Οhyama, Chikara; Irie, Fumitoshi; Yamaguchi, Yu

doi:10.1016/j.jbc.2021.101281

Cited by 30 publications

(29 citation statements)

References 61 publications

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“…These enzymes have been shown to be located at cell surfaces and active in generating pro-inflammatory HA fragments in the ECM [71] , [72] , [73] , [74] . It is of interest that high levels of CEMIP2 were found in the CD4 T cells in the co-cultures, thus implicating these cells in turnover of HA [75] , [76] . In addition, our finding that HAPLN3 was generated by activated CD4 T cells suggests a novel mechanism for the remodeling of the ECM in joint disease.…”

Section: Discussionmentioning

confidence: 99%

Crosstalk between CD4 T cells and synovial fibroblasts from human arthritic joints promotes hyaluronan-dependent leukocyte adhesion and inflammatory cytokine expression in vitro

Kang¹,

Hundhausen²,

Evanko³

et al. 2022

Matrix Biology Plus

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Section: Discussionmentioning

confidence: 99%

Crosstalk between CD4 T cells and synovial fibroblasts from human arthritic joints promotes hyaluronan-dependent leukocyte adhesion and inflammatory cytokine expression in vitro

Kang¹,

Hundhausen²,

Evanko³

et al. 2022

Matrix Biology Plus

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“…More recently the protein transmembrane 2 (TMEM2) was shown to have significant hyaluronidase activity (22). TMEM2 is highly expressed in endothelial cells, at least of dermal, lymph or liver origin (22,23) and functions to degrade free plasma HA in the liver (23). At present, it is unclear if TMEM2 instigates HA shedding or degradation during inflammation in nonliver blood vessels.…”

Section: Hyaluronic Acidmentioning

confidence: 99%

Endothelial Glycocalyx Degradation in Critical Illness and Injury

2022

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The endothelial glycocalyx is a gel-like layer on the luminal side of blood vessels that is composed of glycosaminoglycans and the proteins that tether them to the plasma membrane. Interest in its properties and function has grown, particularly in the last decade, as its importance to endothelial barrier function has come to light. Endothelial glycocalyx studies have revealed that many critical illnesses result in its degradation or removal, contributing to endothelial dysfunction and barrier break-down. Loss of the endothelial glycocalyx facilitates the direct access of immune cells and deleterious agents (e.g., proteases and reactive oxygen species) to the endothelium, that can then further endothelial cell injury and dysfunction leading to complications such as edema, and thrombosis. Here, we briefly describe the endothelial glycocalyx and the primary components thought to be directly responsible for its degradation. We review recent literature relevant to glycocalyx damage in several critical illnesses (sepsis, COVID-19, trauma and diabetes) that share inflammation as a common denominator with actions by several common agents (hyaluronidases, proteases, reactive oxygen species, etc.). Finally, we briefly cover strategies and therapies that show promise in protecting or helping to rebuild the endothelial glycocalyx such as steroids, protease inhibitors, anticoagulants and resuscitation strategies.

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“…Albeit the mechanism of UV-induced hyaluronan degradation is less known. Moreover, TMEM2 (transmembrane protein 2) and HYBID (hyaluronan binding protein involved in hyaluronan depolymerization, also known as CEMIP or KIIAA1199) are also able to depolymerize hyaluronan (74,75). TMEM2 degrades extracellular hyaluronan in a Ca 2+ -dependent manner into intermediate-sized fragments which are thereafter internalized and completely degraded in the lysosomes (76).…”

Section: Hyaluronan Hyaluronan and Its Synthesismentioning

confidence: 99%

The Impact of Hyaluronan on Tumor Progression in Cutaneous Melanoma

et al. 2022

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The incidence of cutaneous melanoma is rapidly increasing worldwide. Cutaneous melanoma is an aggressive type of skin cancer, which originates from malignant transformation of pigment producing melanocytes. The main risk factor for melanoma is ultraviolet (UV) radiation, and thus it often arises from highly sun-exposed skin areas and is characterized by a high mutational burden. In addition to melanoma-associated mutations such as BRAF, NRAS, PTEN and cell cycle regulators, the expansion of melanoma is affected by the extracellular matrix surrounding the tumor together with immune cells. In the early phases of the disease, hyaluronan is the major matrix component in cutaneous melanoma microenvironment. It is a high-molecular weight polysaccharide involved in several physiological and pathological processes. Hyaluronan is involved in the inflammatory reactions associated with UV radiation but its role in melanomagenesis is still unclear. Although abundant hyaluronan surrounds epidermal and dermal cells in normal skin and benign nevi, its content is further elevated in dysplastic lesions and local tumors. At this stage hyaluronan matrix may act as a protective barrier against melanoma progression, or alternatively against immune cell attack. While in advanced melanoma, the content of hyaluronan decreases due to altered synthesis and degradation, and this correlates with poor prognosis. This review focuses on hyaluronan matrix in cutaneous melanoma and how the changes in hyaluronan metabolism affect the progression of melanoma.

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The cell surface hyaluronidase TMEM2 is essential for systemic hyaluronan catabolism and turnover

Cited by 30 publications

References 61 publications

Crosstalk between CD4 T cells and synovial fibroblasts from human arthritic joints promotes hyaluronan-dependent leukocyte adhesion and inflammatory cytokine expression in vitro

Crosstalk between CD4 T cells and synovial fibroblasts from human arthritic joints promotes hyaluronan-dependent leukocyte adhesion and inflammatory cytokine expression in vitro

Endothelial Glycocalyx Degradation in Critical Illness and Injury

The Impact of Hyaluronan on Tumor Progression in Cutaneous Melanoma

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