FtsH proteases (FtsHs) belong to intramembrane ATP-dependent metalloproteases which are widely distributed in eubacteria, mitochondria and chloroplasts. The best-studied roles of FtsH in Escherichia coli include quality control of membrane proteins, regulation of response to heat shock, superoxide stress and viral infection, and control of lipopolysaccharide biosynthesis. While heterotrophic bacteria mostly contain a single indispensable FtsH complex, photosynthetic cyanobacteria usually contain three FtsH complexes: two heterocomplexes and one homocomplex. The essential cytoplasmic FtsH1/3 most probably fulfills a role similar to other bacterial FtsHs, whereas the thylakoid FtsH2/3 heterocomplex and FtsH4 homocomplex appear to maintain the photosynthetic apparatus of cyanobacteria and optimize its functionality. Moreover, recent studies suggest the involvement of all FtsH proteases in a complex response to nutrient stresses. In this review, we aim to comprehensively evaluate the functions of the cyanobacterial FtsHs specifically under stress conditions with emphasis on nutrient deficiency and high irradiance. We also point to various unresolved issues concerning FtsH functions, which deserve further attention.

Institute of Microbiology of the Czech Academy of Sciences Centre Algatech Opatovický Mlýn Novohradská 237 Třeboň 37901 The Czech Republic

See more in PubMed

Adam  Z., Halperin  T., Itzhaki  H., Lindahl  M., Ostersetzer  O. (1998) The proteolytic machinery of chloroplasts: homologues of bacterial proteases.

Adam  Z., Rudella  A. and van Wijk  K.J. (2006) Recent advances in the study of Clp, FtsH and other proteases located in chloroplasts. PubMed

Arends  J., Thomanek  N., Kuhlmann  K., Marcus  K. and Narberhaus  F. (2016) In vivo trapping of FtsH substrates by label-free quantitative proteomics. PubMed

Bečková  M., Gardian  Z., Yu  J.F., Koník  P., Nixon  P.J. and Komenda  J. (2017a) Association of Psb28 and Psb27 proteins with PSII-PSI supercomplexes upon exposure of PubMed

Bečková  M., Yu  J., Krynická  V., Kozlo  A., Shao  S., Koník  P., et al. (2017b) Structure of Psb29/Thf1 and its association with the FtsH protease complex involved in photosystem II repair in cyanobacteria. PubMed PMC

Boehm  M., Nield  J., Zhang  P., Aro  E.M., Komenda  J. and Nixon  P.J. (2009) Structural and mutational analysis of band 7 proteins in the cyanobacterium PubMed PMC

Boehm  M., Yu  J., Krynická  V., Barker  M., Tichý  M., Komenda  J., et al. (2012) Subunit organization of a PubMed PMC

Bonisteel  E.M., Turner  B.E., Murphy  C.D., Melanson  J.R., Duff  N.M., Beardsall  B.D., et al. (2018) Strain specific differences in rates of photosystem II repair in picocyanobacteria correlate to differences in FtsH protein levels and isoform expression patterns. PubMed PMC

Bryant  J.A., Sellars  L.E., Busby  S.J. and Lee  D.J. (2014) Chromosome position effects on gene expression in PubMed PMC

Burnap  R.L., Hagemann  M. and Kaplan  A. (2015) Regulation of CO PubMed PMC

Dühring  U., Axmann  I.M., Hess  W.R. and Wilde  A. (2006) An internal antisense RNA regulates expression of the photosynthesis gene PubMed PMC

Espinosa  J., Forchhammer  K. and Contreras  A. (2007) Role of the PubMed

Espinosa  J., Rodriguez-Mateos  F., Salinas  P., Lanza  V.F., Dixon  R., de la Cruz  F., et al. (2014) PipX, the coactivator of NtcA, is a global regulator in cyanobacteria. PubMed PMC

Ferro  M., Brugière  S., Salvi  D., Seigneurin-Berny  D., Court  M., Moyet  L., et al. (2010) AT_CHLORO, a comprehensive chloroplast proteome database with subplastidial localization and curated information on envelope proteins. PubMed PMC

Ferro  M., Salvi  D., Brugière  S., Miras  S., Kowalski  S., Louwagie  M., et al. (2003) Proteomics of the chloroplast envelope membranes from PubMed

Fillat  M.F. (2014) The FUR (ferric uptake regulator) superfamily: diversity and versatility of key transcriptional regulators. PubMed

Fokina  O., Herrmann  C. and Forchhammer  K. (2011) Signal-transduction protein PII from PubMed

Forchhammer  K., Huergo  L.F. and Huergo  L.F. (2022) New views on PII signaling: from nitrogen sensing to global metabolic control. PubMed

Forchhammer  K. and Selim  K.A. (2020) Carbon/nitrogen homeostasis control in cyanobacteria. PubMed PMC

Fu  W., Cui  Z., Guo  J., Cui  X., Han  G., Zhu  Y., et al. (2023) Immunophilin CYN28 is required for accumulation of photosystem II and thylakoid FtsH protease in PubMed PMC

Gómez-Baena  G., Rangel  O.A., López-Lozano  A., García-Fernández  J.M. and Diez  J. (2009) Stress responses in PubMed

Gonzalez  A., Espinosa Angarica  V., Sancho  J. and Fillat  M.F. (2014) The FurA regulon in PubMed PMC

Gonzalez  A., Teresa Bes  M., Luisa Peleato  M., Fillat  M.F. and Hess  W.R. (2016) Expanding the role of FurA as essential global regulator in cyanobacteria. PubMed PMC

Hagemann  M., Song  S., Brouwer  E.-M. (2021) Inorganic carbon assimilation in cyanobacteria: mechanisms, regulation, and engineering.

Huergo  L.F. and Dixon  R. (2015) The emergence of 2-oxoglutarate as a master regulator metabolite. PubMed PMC

Ito  K. and Akiyama  Y. (2005) Cellular functions, mechanism of action, and regulation of FtsH protease. PubMed

Jackson  P.J., Hitchcock  A., Brindley  A.A., Dickman  M.J. and Hunter  C.N. (2023) Absolute quantification of cellular levels of photosynthesis-related proteins in PubMed PMC

Janska  H., Kwasniak  M. and Szczepanowska  J. (2013) Protein quality control in organelles – AAA/FtsH story. PubMed

Jia  A., Zheng  Y., Chen  H. and Wang  Q. (2021) Regulation and functional complexity of the chlorophyll-binding protein IsiA. PubMed PMC

Kaplan  A., Ronen-Tarazi  M., Tchernov  D., Bonfil  D.J., Zer  H., Schatz  D., et al. (1999) The inorganic carbon-concentrating mechanism of cyanobacteria.

Kato  Y., Kuroda  H., Ozawa  S.I., Saito  K., Dogra  V., Scholz  M., et al. (2023) Characterization of tryptophan oxidation affecting D1 degradation by FtsH in the photosystem II quality control of chloroplasts. PubMed PMC

Kato  Y. and Sakamoto  W. (2018) FtsH protease in the thylakoid membrane: physiological functions and the regulation of protease activity. PubMed PMC

Kato  Y. and Sakamoto  W. (2019) Phosphorylation of the chloroplastic metalloprotease FtsH in PubMed PMC

Keren  N., Ohkawa  H., Welsh  E.A., Liberton  M. and Pakrasi  H.B. (2005) Psb29, a conserved 22-kD protein, functions in the biogenesis of photosystem II complexes in PubMed PMC

Kihara  A., Akiyama  Y. and Ito  K. (1996) A protease complex in the Escherichia coli plasma membrane: HflKC (HflA) forms a complex with FtsH (HflB), regulating its proteolytic activity against SecY. PubMed PMC

Klahn  S., Orf  I., Schwarz  D., Matthiessen  J.K., Kopka  J., Hess  W.R., et al. (2015) Integrated transcriptomic and metabolomic characterization of the low-carbon response using an ndhR mutant of PubMed PMC

Kloft  N. and Forchhammer  K. (2005) Signal transduction protein PII phosphatase PphA is required for light-dependent control of nitrate utilization in PubMed PMC

Knoppová  J., Sobotka  R., Yu  J., Bečková  M., Pilný  J., Trinugroho  J.P., et al. (2022) Assembly of D1/D2 complexes of photosystem II: binding of pigments and a network of auxiliary proteins. PubMed PMC

Komenda  J., Barker  M., Kuviková  S., de Vries  R., Mullineaux  C.W., Tichý  M., et al. (2006) The FtsH protease PubMed

Komenda  J., Knoppová  J., Krynická  V., Nixon  P.J. and Tichý  M. (2010) Role of FtsH2 in the repair of photosystem II in mutants of the cyanobacterium PubMed

Komenda  J. and Sobotka  R. (2016) Cyanobacterial high-light-inducible proteins – protectors of chlorophyll-protein synthesis and assembly. PubMed

Komenda  J., Tichý  M., Prášil  O., Knoppová  J., Kuviková  S., de Vries  R., et al. (2007) The exposed N-terminal tail of the D1 subunit is required for rapid D1 degradation during photosystem II repair in PubMed PMC

Koník  P., Skotnicová  P., Gupta  S., Tichý  M., Sharma  S., Komenda  J., et al. (2024) The cyanobacterial FtsH4 protease controls accumulation of protein factors involved in the biogenesis of photosystem I. PubMed

Kopečná  J., Komenda  J., Bučinská  L. and Sobotka  R. (2012) Long-term acclimation of the cyanobacterium PubMed PMC

Kopf  M., Klaehn  S., Scholz  I., Matthiessen  J.K.F., Hess  W.R. and Voss  B. (2014) Comparative analysis of the primary transcriptome of PubMed PMC

Krynická  V., Georg  J., Jackson  P.J., Dickman  M.J., Hunter  C.N., Futschik  M.E., et al. (2019) Depletion of the FtsH1/3 proteolytic complex suppresses the nutrient stress response in the cyanobacterium PubMed PMC

Krynická  V., Shao  S., Nixon  P.J. and Komenda  J. (2015) Accessibility controls selective degradation of photosystem II subunits by FtsH protease. PubMed

Krynická  V., Skotnicová  P., Jackson  P.J., Barnett  S., Yu  J., Wysocka  A., et al. (2023) FtsH4 protease controls biogenesis of the PSII complex by dual regulation of high light-inducible proteins. PubMed PMC

Krynická  V., Tichý  M., Krafl  J., Yu  J., Kaňa  R., Boehm  M., et al. (2014) Two essential FtsH proteases control the level of the Fur repressor during iron deficiency in the cyanobacterium PubMed

Kurisu  G., Zhang  H., Smith  J.L. and Cramer  W.A. (2003) Structure of the cytochrome b6f complex of oxygenic photosynthesis: tuning the cavity. PubMed

Langklotz  S., Baumann  U. and Narberhaus  F. (2012) Structure and function of the bacterial AAA protease FtsH. PubMed

Linhartová  M., Bučinská  L., Halada  P., Ječmen  T., Šetlík  J., Komenda  J., et al. (2014) Accumulation of the Type IV prepilin triggers degradation of SecY and YidC and inhibits synthesis of photosystem II proteins in the cyanobacterium PubMed

Llácer  J.L., Espinosa  J., Castells  M.A., Contreras  A., Forchhammer  K. and Rubio  V. (2010) Structural basis for the regulation of NtcA-dependent transcription by proteins PipX and PII. PubMed PMC

Los  D.A., Zorina  A., Sinetova  M., Kryazhov  S., Mironov  K. and Zinchenko  V.V. (2010) Stress sensors and signal transducers in cyanobacteria. PubMed PMC

Mahbub  M., Hemm  L., Yang  Y., Kaur  R., Carmen  H., Engl  C., et al. (2020) mRNA localization, reaction centre biogenesis and thylakoid membrane targeting in cyanobacteria. PubMed

Malnoë  A., Wang  F., Girard-Bascou  J., Wollman  F.-A. and de Vitry  C. (2014) Thylakoid FtsH protease contributes to photosystem II and cytochrome b(6)f remodeling in PubMed PMC

Mann  N.H., Novac  N., Mullineaux  C.W., Newman  J., Bailey  S. and Robinson  C. (2000) Involvement of an FtsH homologue in the assembly of functional photosystem I in the cyanobacterium PubMed

Maziak  A., Heidorn-Czarna  M., Weremczuk  A. and Janska  H. (2021) FTSH4 and OMA1 mitochondrial proteases reduce moderate heat stress-induced protein aggregation. PubMed PMC

McCleary  W.R. (2017) Molecular mechanisms of phosphate homeostasis in

Muramatsu  M. and Hihara  Y. (2003) Transcriptional regulation of genes encoding subunits of photosystem I during acclimation to high-light conditions in PubMed

Nash  D., Miyao  M. and Murata  N. (1985) Heat inactivation of oxygen evolution in photosystem II particles and its acceleration by chloride depletion and exogenous manganese.

Nevo  R., Charuvi  D., Shimoni  E., Schwarz  R., Kaplan  A., Ohad  I., et al. (2007) Thylakoid membrane perforations and connectivity enable intracellular traffic in cyanobacteria. PubMed PMC

Nixon  P.J., Michoux  F., Yu  J., Boehm  M. and Komenda  J. (2010) Recent advances in understanding the assembly and repair of photosystem II. PubMed PMC

Ogura  T., Inoue  K., Tatsuta  T., Suzaki  T., Karata  K., Young  K., et al. (1999) Balanced biosynthesis of major membrane components through regulated degradation of the committed enzyme of lipid A biosynthesis by the AAA protease FtsH (HflB) in PubMed

Osanai  T. and Tanaka  K. (2007) Keeping in touch with PII: PII-interacting proteins in unicellular cyanobacteria. PubMed

Qiao  Z., Yokoyama  T., Yan  X.F., Beh  I.T., Shi  J., Basak  S., et al. (2022) Cryo-EM structure of the entire FtsH-HflKC AAA protease complex. PubMed

Rachedi  R., Foglino  M. and Latifi  A. (2020) Stress signaling in cyanobacteria: a mechanistic overview. PubMed PMC

Rast  A., Schaffer  M., Albert  S., Wan  W., Pfeffer  S., Beck  F., et al. (2019) Biogenic regions of cyanobacterial thylakoids form contact sites with the plasma membrane. PubMed

Riediger  M., Hernández-Prieto  M.A., Song  K., Hess  W.R. and Futschik  M.E. (2021) Genome-wide identification and characterization of Fur-binding sites in the cyanobacteria PubMed PMC

Riediger  M., Kadowaki  T., Nagayama  R., Georg  J., Hihara  Y. and Hess  W.R. (2019) Biocomputational analyses and experimental validation identify the regulon controlled by the redox-responsive transcription factor RpaB. PubMed PMC

Sacharz  J., Bryan  S.J., Yu  J., Burroughs  N.J., Spence  E.M., Nixon  P.J., et al. (2015) Sub-cellular location of FtsH proteases in the cyanobacterium PubMed PMC

Sakamoto  W. (2003) Coordinated regulation of chloroplastic FTSH metalloproteases VAR1 and VAR2 in

Santos-Beneit  F. (2015) The Pho regulon: a huge regulatory network in bacteria. PubMed PMC

Schwanhäusser  B., Busse  D., Li  N., Dittmar  G., Schuchhardt  J., Wolf  J., et al. (2011) Global quantification of mammalian gene expression control. PubMed

Shao  S., Cardona  T. and Nixon  P.J. (2018) Early emergence of the FtsH proteases involved in photosystem II repair.

Shen  G., Balasubramanian  R., Wang  T., Wu  Y., Hoffart  L.M., Krebs  C., et al. (2007) SufR coordinates two [4Fe-4S]2+, 1+ clusters and functions as a transcriptional repressor of the sufBCDS operon and an autoregulator of sufR in cyanobacteria. PubMed

Silva  P., Thompson  E., Bailey  S., Kruse  O., Mullineaux  C.W., Robinson  C., et al. (2003) FtsH is involved in the early stages of repair of photosystem II in PubMed PMC

Spät  P., Maček  B. and Forchhammer  K. (2015) Phosphoproteome of the cyanobacterium PubMed PMC

Stirnberg  M., Fulda  S., Huckauf  J., Hagemann  M., Kraemer  R. and Marin  K. (2007) A membrane-bound FtsH protease is involved in osmoregulation in PubMed

Stroebel  D., Choquet  Y., Popot  J.L. and Picot  D. (2003) An atypical haem in the cytochrome b(6)f complex. PubMed

Su  Z., Olman  V. and Xu  Y. (2007) Computational prediction of Pho regulons in cyanobacteria. PubMed PMC

Tomoyasu  T., Gamer  J., Bukau  B., Kanemori  M., Mori  H., Rutman  A.J., et al. (1995) PubMed PMC

Uniacke  J. and Zerges  W. (2007) Photosystem II assembly and repair are differentially localized in PubMed PMC

Vavilin  D., Yao  D. and Vermaas  W. (2007) Small Cab-like proteins retard degradation of photosystem II-associated chlorophyll in PubMed

Weixlbaumer  A., Grünberger  F., Werner  F. and Grohmann  D. (2021) Coupling of transcription and translation in Archaea: cues from the bacterial world. PubMed PMC

Wilde  A. and Hihara  Y. (2016) Transcriptional and posttranscriptional regulation of cyanobacterial photosynthesis. PubMed

Wiśniewski  J.R. and Rakus  D. (2014) Multi-enzyme digestion FASP and the ‘Total Protein Approach’-based absolute quantification of the PubMed

Yamamoto  Y., Aminaka  R., Yoshioka  M., Khatoon  M., Komayama  K., Takenaka  D., et al. (2008) Quality control of photosystem II: impact of light and heat stresses. PubMed

Yeo  W.S., Anokwute  C., Marcadis  P., Levitan  M., Ahmed  M., Bae  Y., et al. (2020) A membrane-bound transcription factor is proteolytically regulated by the AAA+ protease FtsH in PubMed PMC

Zhang  P., Sicora  C.I., Vorontsova  N., Allahverdiyeva  Y., Battchikova  N., Nixon  P.J., et al. (2007) FtsH protease is required for induction of inorganic carbon acquisition complexes in PubMed