Hyaluronan synthase 1: a mysterious enzyme with unexpected functions

Our plain-English summary of Hyaluronan synthase 1: a mysterious enzyme with unexpected functions, by H. Siiskonen, S. Oikari, S. Pasonen-Seppänen, et al (Frontiers in Immunology, 2015).

The study

• Authors: H. Siiskonen, S. Oikari, S. Pasonen-Seppänen, K. Rilla
• Journal: Frontiers in Immunology
• Published: 2015;6:43
• Type of article: Review
• Cited by: 95 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Hyaluronan synthase 1 (HAS1) is one of three isoenzymes responsible for cellular hyaluronan synthesis. Interest in HAS1 has been limited because its role in hyaluronan production seems to be insignificant compared to the two other isoenzymes, HAS2 and HAS3, which have higher enzymatic activity. Furthermore, in most cell types studied so far, the expression of its gene is low and the enzyme requires high concentrations of sugar precursors for hyaluronan synthesis, even when overexpressed in cell cultures. Both expression and activity of HAS1 are induced by pro-inflammatory factors like interleukins and cytokines, suggesting its involvement in inflammatory conditions. Has1 is upregulated in states associated with inflammation, like atherosclerosis, osteoarthritis, and infectious lung disease. In addition, both full length and splice variants of HAS1 are expressed in malignancies like bladder and prostate cancers, multiple myeloma, and malignant mesothelioma. Interestingly, immunostainings of tissue sections have demonstrated the role of HAS1 as a poor predictor in breast cancer, and is correlated with high relapse rate and short overall survival. Utilization of fluorescently tagged proteins has revealed the intracellular distribution pattern of HAS1, distinct from other isoenzymes. In all cell types studied so far, a high proportion of HAS1 is accumulated intracellularly, with a faint signal detected on the plasma membrane and its protrusions. Furthermore, the pericellular hyaluronan coat produced by HAS1 is usually thin without induction by inflammatory agents or glycemic stress and depends on CD44-HA interactions. These specific interactions regulate the organization of hyaluronan into a leukocyte recruiting matrix during inflammatory responses. Despite the apparently minor enzymatic activity of HAS1 under normal conditions, it may be an important factor under conditions associated with glycemic stress like metabolic syndrome, inflammation, and cancer.

In plain English

This article was a review, not an original study, and it did not study asbestos or asbestos-exposed people. The authors summarized published research on hyaluronan synthase 1 (HAS1), one of three enzymes that make hyaluronan, a sugar-based substance found around cells and in tissues. The review reported earlier findings that HAS1 sits mostly inside cells and needs more of its sugar building blocks than the other two enzymes, HAS2 and HAS3. It also reported that inflammatory signals such as cytokines switch HAS1 on. It described studies linking HAS1 with inflammation and, in several cancers, linking higher HAS1 expression with poorer patient survival. The abstract listed malignant mesothelioma among cancers that express HAS1, but the main text did not discuss mesothelioma or asbestos further. The authors concluded that, although HAS1 seems to have minor activity under normal conditions, it may be an important factor under high-sugar (glycemic) stress, inflammation and cancer. They noted that cell types expressing only HAS1 were not available for study, that reliable antibodies were lacking, and that some results conflicted.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Review of published research on the enzyme hyaluronan synthase 1 (HAS1)
• Who was studied: No study population. The authors reviewed published studies of HAS1 in cell cultures, animal models and human tissues.
• Exposure: No asbestos or fiber exposure was studied. The review covered factors that regulate HAS1, such as pro-inflammatory cytokines, growth factors and sugar precursor levels.
• Main results:
  • The review reported earlier findings that the HAS1 signal in cells is mainly inside the cell (cytoplasmic) rather than on the cell surface.
  • The review reported an earlier finding that Has1 has lower affinity for its sugar substrate UDP-GlcUA than the other enzymes, with a Km about double that of Has2 and Has3.
  • The authors stated that recent results suggest HAS1 may play a pivotal role during cell stress such as inflammation.
  • Cited studies associated increased HAS1 expression with poor patient survival in ovarian cancer, colon cancer, Waldenström's macroglobulinemia and multiple myeloma.
  • The abstract stated that full-length and splice variants of HAS1 are expressed in malignancies including malignant mesothelioma. The main text mentioned only that HAS1 immunostainings showed notable HAS1 levels in mesothelial cells.
• The authors' conclusion: The authors concluded that, despite its apparently minor enzymatic activity under normal conditions, HAS1 may be an important factor under conditions associated with glycemic stress, such as metabolic syndrome, inflammation and cancer.
• Limitations the authors state:
  • Cell types expressing only HAS1 were not available for study, which made it challenging to study the specific contribution of HAS1.
  • Studies of where HAS enzymes are found in tissues have been hampered by a lack of reliable antibodies and low expression levels.
  • Contradictory results leave open questions about the exact role of HAS1.

Topics

Medical terms in this study, explained in our Lexicon: Interleukins, Cytokine, Inflammation, Myeloma, Mesothelioma, Overall Survival.

Related studies

• Prognostic value of midkine, syndecan-1, hyaluronan synthase-2, sestrin-1, laminin subunit alpha-4 and fibulin-3 for malignant pleural mesothelioma — H. Akgun, S. Metintas, et al. (2023)
• Mysterious link between iron overload and CDKN2A/2B — S. Toyokuni (2011)
• Mysterious pleural effusions — (1982)
• Serum hyaluronan as a disease marker — T.C. Laurent, U.B. Laurent, et al. (1996)
• Extracellular superoxide dismutase inhibits inflammation by preventing oxidative fragmentation of hyaluronan — F. Gao, J.R. Koenitzer, et al. (2008)
• CD44 and its ligand hyaluronan as potential biomarkers in malignant pleural mesothelioma: evidence and perspectives — L. Cortes-Dericks, R.A. Schmid (2017)

Browse more research in Frontiers in Immunology, or return to medical research.